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Masete KV, Massarani AS, Schulzke JD, Epple HJ, Hering NA. Tumour necrosis factor-α induces macromolecule translocation in HIV-derived duodenal organoids. Front Immunol 2025; 16:1563702. [PMID: 40170863 PMCID: PMC11959035 DOI: 10.3389/fimmu.2025.1563702] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2025] [Accepted: 02/26/2025] [Indexed: 04/03/2025] Open
Abstract
Background Disease progression from human immunodeficiency virus (HIV) infection to acquired immunodeficiency syndrome (AIDS) is marked by chronic immune activation, partly due to increased translocation of gut-derived microbial antigens. Elevated mucosal tumour necrosis factor-α (TNF-α) and resulting epithelial cell apoptosis may be the etiology. However, studies using carcinoma cell lines have failed to find a causal link, possibly due to cellular abnormalities related to the malignant transformation of these immortal cell lines. Methods We established intestinal organoid monolayers from healthy controls and HIV-infected adults and characterized their growth dynamics and cellular composition. We then examined the effects of HIV-associated cytokines on transepithelial resistance (TER), apoptosis and macromolecule translocation. Results Organoid monolayers from HIV-infected patients grew similarly to healthy controls, forming confluent monolayers within one to two weeks containing enterocytes, Paneth, goblet and stem cells. IFN-γ synergized with TNF-α, allowing TNF-α to cause caspase-mediated apoptosis and TER reduction within 5 ± 3 hours, reflecting patient sample heterogeneity. This led to paracellular passage of 4 kDa Dextran and transcytosis of 44 kDa horse radish peroxidase, both of which could be blocked by pan-caspase inhibitor, Q-VD-Oph. Conclusion Our study confirms that intestinal organoid monolayers from biopsies of HIV-infected individuals can be used to study apoptosis-related epithelial barrier dysfunction and macromolecular translocation. We provide direct evidence that TNF-α-induced apoptosis triggered two pathways of macromolecular translocation: paracellular passage via apoptotic leaks and transcytosis. Therapies targeting apoptosis may be useful in preventing disease progression from HIV to AIDS.
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Affiliation(s)
- Kopano Valerie Masete
- Department of Gastroenterology, Rheumatology and Infectious Diseases, Clinical Physiology/Nutritional Medicine, Charité – Universitätsmedizin Berlin, Berlin, Germany
| | - Alain S. Massarani
- Department of Gastroenterology, Rheumatology and Infectious Diseases, Clinical Physiology/Nutritional Medicine, Charité – Universitätsmedizin Berlin, Berlin, Germany
| | - Jörg-Dieter Schulzke
- Department of Gastroenterology, Rheumatology and Infectious Diseases, Clinical Physiology/Nutritional Medicine, Charité – Universitätsmedizin Berlin, Berlin, Germany
| | - Hans-Jörg Epple
- Department of Gastroenterology, Rheumatology and Infectious Diseases, Charité – Universitätsmedizin Berlin, Berlin, Germany
- Antibiotic Stewardship Team, Medical Directorate, Charité – Universitätsmedizin Berlin, Berlin, Germany
| | - Nina A. Hering
- Department of General and Visceral Surgery, Charité – Universitätsmedizin Berlin, Berlin, Germany
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2
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Shete AV, Shidhaye P, Rao A, Bhawari N, Deshpande S, Sawant J, Bagul R, Ghule U, Kumbhar S, Ghate M. Differential associations of anti-cytomegalovirus antibodies and soluble CD14 levels with immunosenescence in people living with HIV on long term antiretroviral therapy. Immun Ageing 2024; 21:87. [PMID: 39709460 DOI: 10.1186/s12979-024-00491-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Accepted: 12/09/2024] [Indexed: 12/23/2024]
Abstract
BACKGROUND People living with HIV (PLHIV) demonstrate accelerated aging and immunosenescence in spite of immune-restoration following long-term antiretroviral treatment (ART). Low level inflammation leading to inflammaging plays an important role in mediating premature immunosenescence. Ongoing viral replication, antiretrovirals and subclinical infections with the common viruses like Cytomegalovirus (CMV) are known to induce inflammaging. However such data is scarce in India where persistent low level inflammation is common in general population due to various subclinical infections. Hence we conducted a study to determine the extent of immunosenescence in asymptomatic PLHIV on long term ART in comparison with their age-matched controls. RESULTS The study was conducted in asymptomatic virally suppressed PLHIV on ART for more than 5 years [n = 70, M: F = 36:34] and HIV uninfected controls [n = 68, M: F = 31:37] belonging to the age-group of 40-55 years. Blood samples were collected for assessing levels of immunosenescence markers on CD4 T cells by flow cytometry and anti-CMV antibodies as well as soluble CD14 (sCD14) levels by ELISA. The levels were compared between cases and controls and correlated with the levels of anti-CMV antibody and sCD14. PLHIV had significantly lower levels of naïve T cells and higher levels of activated and immunosenescent T cells than controls as indicated by CD38, CD57, CD28 expressing CD4 and CD8 T cells. PLHIV had higher levels of anti-CMV antibodies, but lower levels of sCD14 levels and HLADR + CD8 T cells than those in controls. Immunosenescent T cells correlated positively with anti-CMV antibody levels and negatively with sCD14 levels. Duration of dolutegravir based therapy correlated negatively with sCD14 levels. CONCLUSIONS Thus, higher levels of immune activation and immunosenescence in the cases possibly indicate their compromised immune status predisposing PLHIV to infections and cancers. The study indicated a need for CMV treatment regimens even in asymptomatic individuals for preventing immunosenescence. The study also indicated a role of dolutegravir induced loss of sCD14 levels in predisposing PLHIV to immunosenescence.
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Affiliation(s)
- Ashwini Vinod Shete
- ICMR-National Institute of Translational Virology and AIDS Research (formerly ICMR-National AIDS Research Institute), 73, G block, MIDC, Bhosari, Pune, 411026, India.
| | - Pallavi Shidhaye
- ICMR-National Institute of Translational Virology and AIDS Research (formerly ICMR-National AIDS Research Institute), 73, G block, MIDC, Bhosari, Pune, 411026, India
| | - Amrita Rao
- ICMR-National Institute of Translational Virology and AIDS Research (formerly ICMR-National AIDS Research Institute), 73, G block, MIDC, Bhosari, Pune, 411026, India
| | - Nikita Bhawari
- ICMR-National Institute of Translational Virology and AIDS Research (formerly ICMR-National AIDS Research Institute), 73, G block, MIDC, Bhosari, Pune, 411026, India
| | - Supriya Deshpande
- ICMR-National Institute of Translational Virology and AIDS Research (formerly ICMR-National AIDS Research Institute), 73, G block, MIDC, Bhosari, Pune, 411026, India
| | - Jyoti Sawant
- ICMR-National Institute of Translational Virology and AIDS Research (formerly ICMR-National AIDS Research Institute), 73, G block, MIDC, Bhosari, Pune, 411026, India
| | - Rajani Bagul
- ICMR-National Institute of Translational Virology and AIDS Research (formerly ICMR-National AIDS Research Institute), 73, G block, MIDC, Bhosari, Pune, 411026, India
| | - Ujjwala Ghule
- ICMR-National Institute of Translational Virology and AIDS Research (formerly ICMR-National AIDS Research Institute), 73, G block, MIDC, Bhosari, Pune, 411026, India
| | - Sunita Kumbhar
- ICMR-National Institute of Translational Virology and AIDS Research (formerly ICMR-National AIDS Research Institute), 73, G block, MIDC, Bhosari, Pune, 411026, India
| | - Manisha Ghate
- ICMR-National Institute of Translational Virology and AIDS Research (formerly ICMR-National AIDS Research Institute), 73, G block, MIDC, Bhosari, Pune, 411026, India
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3
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Capriotti Z, Klase Z. Innate immune memory in chronic HIV and HIV-associated neurocognitive disorders (HAND): potential mechanisms and clinical implications. J Neurovirol 2024; 30:451-476. [PMID: 39733092 PMCID: PMC11846772 DOI: 10.1007/s13365-024-01239-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 11/26/2024] [Accepted: 12/13/2024] [Indexed: 12/30/2024]
Abstract
Although antiretroviral therapy (ART) has dramatically improved the outlook of the HIV/AIDS pandemic, people living with HIV (PLWH) on suppressive therapy are still at higher risk for a range of comorbidities including cardiovascular disease (CVD) and HIV-associated neurocognitive disorders (HAND), among others. Chronic inflammation and immune activation are thought to be an underlying cause of these comorbidities. Many of the factors thought to drive chronic inflammation and immune activation in HIV overlap with factors known to induce trained immunity. Trained immunity is a form of innate immune memory that metabolically and epigenetically reprograms innate immune cells to mount enhanced inflammatory responses upon secondary encounter with unrelated inflammatory stimuli. While this phenotype has been characterized in a variety of disease states in animals and humans, very little is known about its potential contribution to chronic HIV pathogenesis. In this review, a broad overview of innate immune memory in the periphery and the central nervous system (CNS) is provided and the evidence for trained immunity in the context of HIV is considered. In PLWH on ART, this phenotype could contribute to the chronic inflammation and immune activation associated with HIV comorbidities and could complicate HIV cure strategies due to the potential persistence of the phenotype after eradication of the virus. Further research into this immune state in the context of HIV may open the door for new therapeutics aimed at treating HIV comorbidities like HAND.
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Affiliation(s)
- Zachary Capriotti
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA, 19102, USA
- Molecular and Cell Biology and Genetics Graduate Program, Drexel University College of Medicine, Philadelphia, PA, USA
| | - Zachary Klase
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA, 19102, USA.
- Center for Neuroimmunology and CNS Therapeutics, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, PA, USA.
- Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, 19102, USA.
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Qadri H, Shah AH, Almilaibary A, Mir MA. Microbiota, natural products, and human health: exploring interactions for therapeutic insights. Front Cell Infect Microbiol 2024; 14:1371312. [PMID: 39035357 PMCID: PMC11257994 DOI: 10.3389/fcimb.2024.1371312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Accepted: 06/03/2024] [Indexed: 07/23/2024] Open
Abstract
The symbiotic relationship between the human digestive system and its intricate microbiota is a captivating field of study that continues to unfold. Comprising predominantly anaerobic bacteria, this complex microbial ecosystem, teeming with trillions of organisms, plays a crucial role in various physiological processes. Beyond its primary function in breaking down indigestible dietary components, this microbial community significantly influences immune system modulation, central nervous system function, and disease prevention. Despite the strides made in microbiome research, the precise mechanisms underlying how bacterial effector functions impact mammalian and microbiome physiology remain elusive. Unlike the traditional DNA-RNA-protein paradigm, bacteria often communicate through small molecules, underscoring the imperative to identify compounds produced by human-associated bacteria. The gut microbiome emerges as a linchpin in the transformation of natural products, generating metabolites with distinct physiological functions. Unraveling these microbial transformations holds the key to understanding the pharmacological activities and metabolic mechanisms of natural products. Notably, the potential to leverage gut microorganisms for large-scale synthesis of bioactive compounds remains an underexplored frontier with promising implications. This review serves as a synthesis of current knowledge, shedding light on the dynamic interplay between natural products, bacteria, and human health. In doing so, it contributes to our evolving comprehension of microbiome dynamics, opening avenues for innovative applications in medicine and therapeutics. As we delve deeper into this intricate web of interactions, the prospect of harnessing the power of the gut microbiome for transformative medical interventions becomes increasingly tantalizing.
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Affiliation(s)
- Hafsa Qadri
- Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar, India
| | - Abdul Haseeb Shah
- Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar, India
| | - Abdullah Almilaibary
- Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar, India
- Department of Family and Community Medicine, Faculty of Medicine, Al Baha University, Al Bahah, Saudi Arabia
| | - Manzoor Ahmad Mir
- Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar, India
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Hmiel L, Zhang S, Obare LM, Santana MADO, Wanjalla CN, Titanji BK, Hileman CO, Bagchi S. Inflammatory and Immune Mechanisms for Atherosclerotic Cardiovascular Disease in HIV. Int J Mol Sci 2024; 25:7266. [PMID: 39000373 PMCID: PMC11242562 DOI: 10.3390/ijms25137266] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Revised: 06/26/2024] [Accepted: 06/28/2024] [Indexed: 07/16/2024] Open
Abstract
Atherosclerotic vascular disease disproportionately affects persons living with HIV (PLWH) compared to those without. The reasons for the excess risk include dysregulated immune response and inflammation related to HIV infection itself, comorbid conditions, and co-infections. Here, we review an updated understanding of immune and inflammatory pathways underlying atherosclerosis in PLWH, including effects of viral products, soluble mediators and chemokines, innate and adaptive immune cells, and important co-infections. We also present potential therapeutic targets which may reduce cardiovascular risk in PLWH.
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Affiliation(s)
- Laura Hmiel
- Department of Medicine, Division of Infectious Disease, MetroHealth Medical Center and Case Western Reserve University, Cleveland, OH 44109, USA
| | - Suyu Zhang
- Department of Medicine, Emory University, Atlanta, GA 30322, USA
| | - Laventa M. Obare
- Division of Infectious Diseases, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | | | - Celestine N. Wanjalla
- Division of Infectious Diseases, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Boghuma K. Titanji
- Division of Infectious Diseases, Emory University, Atlanta, GA 30322, USA
| | - Corrilynn O. Hileman
- Department of Medicine, Division of Infectious Disease, MetroHealth Medical Center and Case Western Reserve University, Cleveland, OH 44109, USA
| | - Shashwatee Bagchi
- Division of Infectious Diseases, Washington University in St. Louis, St. Louis, MO 63110, USA
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Liu J, Ding C, Shi Y, Wang Y, Zhang X, Huang L, Fang Q, Shuai C, Gao Y, Wu J. Advances in Mechanism of HIV-1 Immune Reconstitution Failure: Understanding Lymphocyte Subpopulations and Interventions for Immunological Nonresponders. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2024; 212:1609-1620. [PMID: 38768409 DOI: 10.4049/jimmunol.2300777] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Accepted: 04/08/2024] [Indexed: 05/22/2024]
Abstract
In individuals diagnosed with AIDS, the primary method of sustained suppression of HIV-1 replication is antiretroviral therapy, which systematically increases CD4+ T cell levels and restores immune function. However, there is still a subset of 10-40% of people living with HIV who not only fail to reach normal CD4+ T cell counts but also experience severe immune dysfunction. These individuals are referred to as immunological nonresponders (INRs). INRs have a higher susceptibility to opportunistic infections and non-AIDS-related illnesses, resulting in increased morbidity and mortality rates. Therefore, it is crucial to gain new insights into the primary mechanisms of immune reconstitution failure to enable early and effective treatment for individuals at risk. This review provides an overview of the dynamics of key lymphocyte subpopulations, the main molecular mechanisms of INRs, clinical diagnosis, and intervention strategies during immune reconstitution failure, primarily from a multiomics perspective.
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Affiliation(s)
- Jiamin Liu
- School of Public Health, Anhui Medical University, Hefei, China
| | - Chengchao Ding
- The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Yu Shi
- School of Public Health, Anhui Medical University, Hefei, China
| | - Yiyu Wang
- School of Public Health, Anhui Medical University, Hefei, China
| | - Xiangyu Zhang
- The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Lina Huang
- The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Qin Fang
- Central Laboratory of HIV Molecular and Immunology, Anhui Provincial Center for Disease Control and Prevention, Hefei, China
| | - Chenxi Shuai
- Central Laboratory of HIV Molecular and Immunology, Anhui Provincial Center for Disease Control and Prevention, Hefei, China
| | - Yong Gao
- The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Jianjun Wu
- School of Public Health, Anhui Medical University, Hefei, China
- Central Laboratory of HIV Molecular and Immunology, Anhui Provincial Center for Disease Control and Prevention, Hefei, China
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Obare LM, Temu T, Mallal SA, Wanjalla CN. Inflammation in HIV and Its Impact on Atherosclerotic Cardiovascular Disease. Circ Res 2024; 134:1515-1545. [PMID: 38781301 PMCID: PMC11122788 DOI: 10.1161/circresaha.124.323891] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/25/2024]
Abstract
People living with HIV have a 1.5- to 2-fold increased risk of developing cardiovascular disease. Despite treatment with highly effective antiretroviral therapy, people living with HIV have chronic inflammation that makes them susceptible to multiple comorbidities. Several factors, including the HIV reservoir, coinfections, clonal hematopoiesis of indeterminate potential (CHIP), microbial translocation, and antiretroviral therapy, may contribute to the chronic state of inflammation. Within the innate immune system, macrophages harbor latent HIV and are among the prominent immune cells present in atheroma during the progression of atherosclerosis. They secrete inflammatory cytokines such as IL (interleukin)-6 and tumor necrosis-α that stimulate the expression of adhesion molecules on the endothelium. This leads to the recruitment of other immune cells, including cluster of differentiation (CD)8+ and CD4+ T cells, also present in early and late atheroma. As such, cells of the innate and adaptive immune systems contribute to both systemic inflammation and vascular inflammation. On a molecular level, HIV-1 primes the NLRP3 (NLR family pyrin domain containing 3) inflammasome, leading to an increased expression of IL-1β, which is important for cardiovascular outcomes. Moreover, activation of TLRs (toll-like receptors) by HIV, gut microbes, and substance abuse further activates the NLRP3 inflammasome pathway. Finally, HIV proteins such as Nef (negative regulatory factor) can inhibit cholesterol efflux in monocytes and macrophages through direct action on the cholesterol transporter ABCA1 (ATP-binding cassette transporter A1), which promotes the formation of foam cells and the progression of atherosclerotic plaque. Here, we summarize the stages of atherosclerosis in the context of HIV, highlighting the effects of HIV, coinfections, and antiretroviral therapy on cells of the innate and adaptive immune system and describe current and future interventions to reduce residual inflammation and improve cardiovascular outcomes among people living with HIV.
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Affiliation(s)
- Laventa M. Obare
- Division of Infectious Diseases, Vanderbilt University Medical Center, Nashville, TN (L.M.O., S.A.M., C.N.W.)
| | - Tecla Temu
- Department of Pathology, Harvard Medical School, Boston, MA (T.T.)
| | - Simon A. Mallal
- Division of Infectious Diseases, Vanderbilt University Medical Center, Nashville, TN (L.M.O., S.A.M., C.N.W.)
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN (S.A.M.)
- Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN (S.A.M.)
- Institute for Immunology and Infectious Diseases, Murdoch University, WA, Western Australia (S.A.M.)
| | - Celestine N. Wanjalla
- Division of Infectious Diseases, Vanderbilt University Medical Center, Nashville, TN (L.M.O., S.A.M., C.N.W.)
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Calado M, Ferreira R, Pires D, Santos-Costa Q, Anes E, Brites D, Azevedo-Pereira JM. Unravelling the triad of neuroinvasion, neurodissemination, and neuroinflammation of human immunodeficiency virus type 1 in the central nervous system. Rev Med Virol 2024; 34:e2534. [PMID: 38588024 DOI: 10.1002/rmv.2534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 03/05/2024] [Accepted: 03/28/2024] [Indexed: 04/10/2024]
Abstract
Since the identification of human immunodeficiency virus type 1 (HIV-1) in 1983, many improvements have been made to control viral replication in the peripheral blood and to treat opportunistic infections. This has increased life expectancy but also the incidence of age-related central nervous system (CNS) disorders and HIV-associated neurodegeneration/neurocognitive impairment and depression collectively referred to as HIV-associated neurocognitive disorders (HAND). HAND encompasses a spectrum of different clinical presentations ranging from milder forms such as asymptomatic neurocognitive impairment or mild neurocognitive disorder to a severe HIV-associated dementia (HAD). Although control of viral replication and suppression of plasma viral load with combination antiretroviral therapy has reduced the incidence of HAD, it has not reversed milder forms of HAND. The objective of this review, is to describe the mechanisms by which HIV-1 invades and disseminates in the CNS, a crucial event leading to HAND. The review will present the evidence that underlies the relationship between HIV infection and HAND. Additionally, recent findings explaining the role of neuroinflammation in the pathogenesis of HAND will be discussed, along with prospects for treatment and control.
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Affiliation(s)
- Marta Calado
- Host-Pathogen Interactions Unit, Research Institute for Medicines, iMed-ULisboa, Faculty of Pharmacy, Universidade de Lisboa, Lisboa, Portugal
| | - Rita Ferreira
- Host-Pathogen Interactions Unit, Research Institute for Medicines, iMed-ULisboa, Faculty of Pharmacy, Universidade de Lisboa, Lisboa, Portugal
| | - David Pires
- Host-Pathogen Interactions Unit, Research Institute for Medicines, iMed-ULisboa, Faculty of Pharmacy, Universidade de Lisboa, Lisboa, Portugal
- Center for Interdisciplinary Research in Health, Católica Medical School, Universidade Católica Portuguesa, Estrada Octávio Pato, Rio de Mouro, Portugal
| | - Quirina Santos-Costa
- Host-Pathogen Interactions Unit, Research Institute for Medicines, iMed-ULisboa, Faculty of Pharmacy, Universidade de Lisboa, Lisboa, Portugal
| | - Elsa Anes
- Host-Pathogen Interactions Unit, Research Institute for Medicines, iMed-ULisboa, Faculty of Pharmacy, Universidade de Lisboa, Lisboa, Portugal
| | - Dora Brites
- Neuroinflammation, Signaling and Neuroregeneration Unit, Research Institute for Medicines, iMed-ULisboa, Faculty of Pharmacy, Universidade de Lisboa, Lisboa, Portugal
| | - José Miguel Azevedo-Pereira
- Host-Pathogen Interactions Unit, Research Institute for Medicines, iMed-ULisboa, Faculty of Pharmacy, Universidade de Lisboa, Lisboa, Portugal
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Grassi G, Notari S, Cicalini S, Casetti R, Cimini E, Bordoni V, Gagliardini R, Mazzotta V, Antinori A, Agrati C, Sacchi A. Brief Report: In cART-Treated HIV-Infected Patients, Immunologic Failure Is Associated With a High Myeloid-Derived Suppressor Cell Frequency. J Acquir Immune Defic Syndr 2024; 95:185-189. [PMID: 38211959 DOI: 10.1097/qai.0000000000003335] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Accepted: 10/10/2023] [Indexed: 01/13/2024]
Abstract
BACKGROUND During HIV infection, effective combined antiretroviral therapy suppresses viral replication and restores the number of circulating CD4+ T cells. However, 15%-30% of treated patients show a discordant response to combined antiretroviral therapy. Myeloid-derived suppressor cells (MDSC) are expanded in HIV+ patients; to better understand the role of MDSC on CD4 T-cell recovery, we evaluated the frequency of MDSC in HIV+ patients under combined antiretroviral therapy and its association with immunologic response. METHODS We enrolled 60 HIV+ patients, including complete responders (R, n = 44), virologic nonresponders (VNR, n = 5), and immunologic nonresponders (INR, n = 11). The frequency of circulating MDSC and the percentage of activated and naïve CD4 T cells were evaluated by flow cytometry. Plasmatic cytokine levels were analyzed by automated ELISA. RESULTS As previously observed, polymorphonuclear MDSC (PMN-MDSC) frequency was higher in HIV+ patients compared with healthy donors. Furthermore, PMN-MDSC percentage was higher in INR than R patients, and a significant association between MDSC frequency and immunologic failure was confirmed by a receiver operator characteristic analysis. Accordingly, an inverse correlation was found between the percentages of PMN-MDSC and naïve CD4 T cells. A positive correlation was observed between PMN-MDSC frequency and the percentage of human leucocyte antigen locus DR + CD4 T cells and the plasmatic level of IL-1β and IL-8. CONCLUSION Our results show that a high frequency of PMN-MDSC persists in INR, possibly because of immune activation, contributing to CD4 T-cell recovery failure. These findings further highlight the detrimental role of MDSC during HIV infection, suggesting these cells as a possible new therapeutic target.
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Affiliation(s)
- Germana Grassi
- Cellular Immunology and Pharmacology Laboratory, National Institute for Infectious Diseases "Lazzaro Spallanzani", Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
| | - Stefania Notari
- Cellular Immunology and Pharmacology Laboratory, National Institute for Infectious Diseases "Lazzaro Spallanzani", Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
| | - Stefania Cicalini
- Clinical Division, National Institute for Infectious Diseases "Lazzaro Spallanzani", Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
| | - Rita Casetti
- Cellular Immunology and Pharmacology Laboratory, National Institute for Infectious Diseases "Lazzaro Spallanzani", Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
| | - Eleonora Cimini
- Cellular Immunology and Pharmacology Laboratory, National Institute for Infectious Diseases "Lazzaro Spallanzani", Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
| | - Veronica Bordoni
- Oncoematologia e Officina Farmaceutica, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Bambino Gesù Children's Hospital, Roma, Italy; and
| | - Roberta Gagliardini
- Clinical Division, National Institute for Infectious Diseases "Lazzaro Spallanzani", Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
| | - Valentina Mazzotta
- Clinical Division, National Institute for Infectious Diseases "Lazzaro Spallanzani", Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
| | - Andrea Antinori
- Clinical Division, National Institute for Infectious Diseases "Lazzaro Spallanzani", Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
| | - Chiara Agrati
- Oncoematologia e Officina Farmaceutica, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Bambino Gesù Children's Hospital, Roma, Italy; and
| | - Alessandra Sacchi
- Molecular Virology and Antimicrobial Immunity Laboratory, Department of Science, Roma Tre University, Rome, Italy
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Munjoma PT, Chandiwana P, Wyss J, Mazhandu AJ, Jordi SBU, Gutsire R, Katsidzira L, Yilmaz B, Misselwitz B, Duri K. Immune activation and inflammation in lactating women on combination antiretroviral therapy: role of gut dysfunction and gut microbiota imbalance. Front Immunol 2023; 14:1280262. [PMID: 38045684 PMCID: PMC10693333 DOI: 10.3389/fimmu.2023.1280262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Accepted: 10/17/2023] [Indexed: 12/05/2023] Open
Abstract
Introduction Combination antiretroviral therapy (cART) effectively controls HIV; however, chronic low-level viremia and gut microbiota dysbiosis remain significant drivers of gut and systemic inflammation. In this study, we explored the relationship between gut microbiota composition, intestinal inflammation, microbial translocation, and systemic inflammation in women on cART in Sub-Saharan Africa. Methods We conducted a study in HIV-infected and HIV-uninfected lactating women followed up at 6 weeks and 6 months postpartum in Harare, Zimbabwe. We used 16S ribosomal Ribonucleic Acid (rRNA) sequencing and MesoScale Discovery V-Plex assays to examine the gut microbiome and to quantify plasma inflammatory biomarkers, respectively. In addition, we measured fecal calprotectin, plasma lipopolysaccharide-binding protein (LBP), and soluble cluster of differentiation 14 (sCD14) by enzyme-linked immunosorbent assay to assess gut inflammation, microbial translocation, and monocyte/macrophage activation. Results A group of 77 lactating women were studied, of which 35% were HIV-infected. Fecal calprotectin levels were similar by HIV status at both follow-up time points. In the HIV-infected group at 6 weeks postpartum, fecal calprotectin was elevated: median (interquartile range) [158.1 µg/g (75.3-230.2)] in women who had CD4+ T-lymphocyte counts <350 cells/µL compared with those with ≥350 cells/µL [21.1 µg/g (0-58.4)], p = 0.032. Plasma sCD14 levels were significantly higher in the HIV-infected group at both 6 weeks and 6 months postpartum, p < 0.001. Plasma LBP levels were similar, but higher levels were observed in HIV-infected women with elevated fecal calprotectin. We found significant correlations between fecal calprotectin, LBP, and sCD14 with proinflammatory cytokines. Gut microbial alpha diversity was not affected by HIV status and was not affected by use of antibiotic prophylaxis. HIV significantly affected microbial beta diversity, and significant differences in microbial composition were noted. The genera Slackia and Collinsella were relatively more abundant in the HIV-infected group, whereas a lower relative abundance of Clostriduim sensu_stricto_1 was observed. Our study also found correlations between gut microbial taxa abundance and systemic inflammatory biomarkers. Discussion and conclusion HIV-infected lactating women had increased immune activation and increased microbial translocation associated with increased gut inflammation. We identified correlations between the gut inflammation and microbial composition, microbial translocation, and systemic inflammation. The interplay of these parameters might affect the health of this vulnerable population.
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Affiliation(s)
- Privilege Tendai Munjoma
- Immunology Unit, Department of Laboratory Diagnostic and Investigative Sciences, University of Zimbabwe Faculty of Medicine and Health Sciences (UZ-FMHS), Harare, Zimbabwe
| | - Panashe Chandiwana
- Immunology Unit, Department of Laboratory Diagnostic and Investigative Sciences, University of Zimbabwe Faculty of Medicine and Health Sciences (UZ-FMHS), Harare, Zimbabwe
| | - Jacqueline Wyss
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
- Department for Biomedical Research, Maurice Müller Laboratories, University of Bern, Bern, Switzerland
| | - Arthur John Mazhandu
- Immunology Unit, Department of Laboratory Diagnostic and Investigative Sciences, University of Zimbabwe Faculty of Medicine and Health Sciences (UZ-FMHS), Harare, Zimbabwe
| | - Sebastian Bruno Ulrich Jordi
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
- Department for Biomedical Research, Maurice Müller Laboratories, University of Bern, Bern, Switzerland
| | - Rutendo Gutsire
- Immunology Unit, Department of Laboratory Diagnostic and Investigative Sciences, University of Zimbabwe Faculty of Medicine and Health Sciences (UZ-FMHS), Harare, Zimbabwe
| | - Leolin Katsidzira
- Department of Internal Medicine, University of Zimbabwe Faculty of Medicine and Health Sciences (UZ-FMHS), Harare, Zimbabwe
| | - Bahtiyar Yilmaz
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
- Department for Biomedical Research, Maurice Müller Laboratories, University of Bern, Bern, Switzerland
| | - Benjamin Misselwitz
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
- Department for Biomedical Research, Maurice Müller Laboratories, University of Bern, Bern, Switzerland
| | - Kerina Duri
- Immunology Unit, Department of Laboratory Diagnostic and Investigative Sciences, University of Zimbabwe Faculty of Medicine and Health Sciences (UZ-FMHS), Harare, Zimbabwe
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11
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Enriquez AB, Ten Caten F, Ghneim K, Sekaly RP, Sharma AA. Regulation of Immune Homeostasis, Inflammation, and HIV Persistence by the Microbiome, Short-Chain Fatty Acids, and Bile Acids. Annu Rev Virol 2023; 10:397-422. [PMID: 37774124 DOI: 10.1146/annurev-virology-040323-082822] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/01/2023]
Abstract
Despite antiretroviral therapy (ART), people living with human immunodeficiency virus (HIV) (PLWH) continue to experience chronic inflammation and immune dysfunction, which drives the persistence of latent HIV and prevalence of clinical comorbidities. Elucidating the mechanisms that lead to suboptimal immunity is necessary for developing therapeutics that improve the quality of life of PLWH. Although previous studies have found associations between gut dysbiosis and immune dysfunction, the cellular/molecular cascades implicated in the manifestation of aberrant immune responses downstream of microbial perturbations in PLWH are incompletely understood. Recent literature has highlighted that two abundant metabolite families, short-chain fatty acids (SCFAs) and bile acids (BAs), play a crucial role in shaping immunity. These metabolites can be produced and/or modified by bacterial species that make up the gut microbiota and may serve as the causal link between changes to the gut microbiome, chronic inflammation, and immune dysfunction in PLWH. In this review, we discuss our current understanding of the role of the microbiome on HIV acquisition and latent HIV persistence despite ART. Further, we describe cellular/molecular cascades downstream of SCFAs and BAs that drive innate or adaptive immune responses responsible for promoting latent HIV persistence in PLWH. This knowledge can be used to advance HIV cure efforts.
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Affiliation(s)
- Ana Beatriz Enriquez
- Pathology Advanced Translational Research Unit, Department of Pathology, Emory University School of Medicine, Atlanta, Georgia, USA;
| | - Felipe Ten Caten
- Pathology Advanced Translational Research Unit, Department of Pathology, Emory University School of Medicine, Atlanta, Georgia, USA;
| | - Khader Ghneim
- Pathology Advanced Translational Research Unit, Department of Pathology, Emory University School of Medicine, Atlanta, Georgia, USA;
| | - Rafick-Pierre Sekaly
- Pathology Advanced Translational Research Unit, Department of Pathology, Emory University School of Medicine, Atlanta, Georgia, USA;
| | - Ashish Arunkumar Sharma
- Pathology Advanced Translational Research Unit, Department of Pathology, Emory University School of Medicine, Atlanta, Georgia, USA;
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Krug SM, Grünhagen C, Allers K, Bojarski C, Seybold J, Schneider T, Schulzke JD, Epple HJ. Macromolecule Translocation across the Intestinal Mucosa of HIV-Infected Patients by Transcytosis and through Apoptotic Leaks. Cells 2023; 12:1887. [PMID: 37508551 PMCID: PMC10378197 DOI: 10.3390/cells12141887] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 07/13/2023] [Accepted: 07/14/2023] [Indexed: 07/30/2023] Open
Abstract
Based on indirect evidence, increased mucosal translocation of gut-derived microbial macromolecules has been proposed as an important pathomechanism in HIV infection. Here, we quantified macromolecule translocation across intestinal mucosa from treatment-naive HIV-infected patients, HIV-infected patients treated by combination antiretroviral therapy, and HIV-negative controls and analyzed the translocation pathways involved. Macromolecule permeability was quantified by FITC-Dextran 4000 (FD4) and horseradish peroxidase (HRP) flux measurements. Translocation pathways were addressed using cold inhibition experiments. Tight junction proteins were characterized by immunoblotting. Epithelial apoptosis was quantified and translocation pathways were further characterized by flux studies in T84 cell monolayers using inducers and inhibitors of apoptosis and endocytosis. In duodenal mucosa of untreated but not treated HIV-infected patients, FD4 and HRP permeabilities were more than a 4-fold increase compared to the HIV-negative controls. Duodenal macromolecule permeability was partially temperature-dependent and associated with epithelial apoptosis without altered expression of the analyzed tight junction proteins. In T84 monolayers, apoptosis induction increased, and both apoptosis and endocytosis inhibitors reduced macromolecule permeability. Using quantitative analysis, we demonstrate the increased macromolecule permeability of the intestinal mucosa in untreated HIV-infected patients. Combining structural and mechanistic studies, we identified two pathways of increased macromolecule translocation in HIV infection: transcytosis and passage through apoptotic leaks.
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Affiliation(s)
- Susanne M Krug
- Clinical Physiology/Nutritional Medicine, Charité-Universitätsmedizin Berlin, 12203 Berlin, Germany
| | - Carolin Grünhagen
- Department of Gastroenterology, Rheumatology and Infectious Diseases, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, 12203 Berlin, Germany
| | - Kristina Allers
- Department of Gastroenterology, Rheumatology and Infectious Diseases, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, 12203 Berlin, Germany
| | - Christian Bojarski
- Department of Gastroenterology, Rheumatology and Infectious Diseases, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, 12203 Berlin, Germany
| | - Joachim Seybold
- Antibiotic Stewardship Team, Medical Directorate, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany
| | - Thomas Schneider
- Department of Gastroenterology, Rheumatology and Infectious Diseases, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, 12203 Berlin, Germany
| | - Jörg-Dieter Schulzke
- Clinical Physiology/Nutritional Medicine, Charité-Universitätsmedizin Berlin, 12203 Berlin, Germany
- Department of Gastroenterology, Rheumatology and Infectious Diseases, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, 12203 Berlin, Germany
| | - Hans-Jörg Epple
- Department of Gastroenterology, Rheumatology and Infectious Diseases, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, 12203 Berlin, Germany
- Antibiotic Stewardship Team, Medical Directorate, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany
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Gong K, Lai Y. Development trends of immune activation during HIV infection in recent three decades: a bibliometric analysis based on CiteSpace. Arch Microbiol 2023; 205:283. [PMID: 37432538 DOI: 10.1007/s00203-023-03624-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 06/18/2023] [Accepted: 07/02/2023] [Indexed: 07/12/2023]
Abstract
This study aimed to evaluate and pinpoint the status, hot areas, and frontiers of immune activation during HIV infection utilizing CiteSpace. From 1990 to 2022, we searched for studies on immune activation during HIV infection in the Web of Science Core Collection. CiteSpace was used to visually analyze the publications to identify the research status and pertinent research hotspots and frontiers in terms of the countries, institutions, authors, references, journals, and keywords. The Web of Science Core Collection yielded 5321 articles on immune activation during HIV infection. With 2854 and 364 articles, the United States and the University of California, San Francisco were the leading nation and institution in this domain. Steven G. Deeks has published 95 papers and is the most published author. The top cited articles on microbial translocation as a significant factor during HIV infection were published by Brenchley et al. Research on molecular/biology/genetics is often referenced in publications in the journals of molecular/biology/immunology. Inflammation, risk, mortality, cardiovascular disease, persistence, and biomarkers will be high-frequency words that are hot topics of research. According to the results, there was a strong collaboration between countries and organizations but little collaboration among authors. Molecular biology, immunology, and medicine are the main study subjects. The current hot topics in research are inflammation, risk, mortality, cardiovascular disease, persistence, and biomarkers. Future studies should concentrate on reducing the pathological changes caused by inflammation and altering the mechanisms of immune activation to reduce the size of the viral reservoir.
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Affiliation(s)
- Kang Gong
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Yu Lai
- School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
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Naz S, Ali Z, Minhas A, Fatima A, Waseem S. Generation of dysbiotic microbiota in cutaneous Leishmaniasis and enhancement of skin inflammation. Microb Pathog 2023; 181:106202. [PMID: 37327948 DOI: 10.1016/j.micpath.2023.106202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 06/12/2023] [Accepted: 06/13/2023] [Indexed: 06/18/2023]
Abstract
Cutaneous Leishmaniasis (CL) affects millions of people globally and has a significant impact on morbidity and mortality. Innate immune mediators are likely to influence the clinical phenotype of CL through primary responses that restrict or facilitate parasite spread. The aim of the study was to bring to attention the significance of microbiota in the development of CL and emphasized the necessity of including the role of microbiota in CL while promoting a One Health approach for managing diseases. To achieve this, we used 16S amplicon metagenome sequencing and QIIME2 pipeline to analyze the microbiome composition of CL-infected patients compared to non-infected, healthy subjects. 16S sequencing analysis showed serum microbiome was dominated by Firmicutes, Proteobacteria, Bacteroidota, and Actinobacteria. CL-infected individuals, Proteobacteria were the most prevalent (27.63 ± 9.79), with the relative abundance (10.73 ± 5.33) of Proteobacteria in control. Bacilli class was found to be the most prevalent in healthy controls (30.71 ± 8.44) while (20.57 ± 9.51) in CL-infected individuals. The class Alphaproteobacteria was found to be more in CL-infected individuals (5.47 ± 2.07) as compared to healthy controls (1.85 ± 0.39). The CL-infected individuals had a significantly lower relative abundance of the Clostridia class (p < 0.0001). An altered serum microbiome of CL infection and higher microbial abundance in the serum of healthy individuals was observed.
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Affiliation(s)
- Shumaila Naz
- Department of Biological Sciences, National University of Medical Sciences (NUMS), Rawalpindi, 46000, Pakistan.
| | - Zain Ali
- ABO SCIENTIFIC, Chakri Road, Rawalpindi, Pakistan
| | - Azhar Minhas
- Department of Dermatology, Combined Military Hospital (CMH), Quetta, 87300, Pakistan
| | - Anam Fatima
- Department of Medicine, Polyclinic Hospital, Islamabad, Pakistan
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15
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Goosen C, Proost S, Baumgartner J, Mallick K, Tito RY, Barnabas SL, Cotton MF, Zimmermann MB, Raes J, Blaauw R. Associations of HIV and iron status with gut microbiota composition, gut inflammation and gut integrity in South African school-age children: a two-way factorial case-control study. J Hum Nutr Diet 2023; 36:819-832. [PMID: 36992541 PMCID: PMC10946596 DOI: 10.1111/jhn.13171] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Accepted: 03/19/2023] [Indexed: 03/31/2023]
Abstract
BACKGROUND Human immunodeficiency virus (HIV) and iron deficiency (ID) affect many African children. Both HIV and iron status interact with gut microbiota composition and related biomarkers. The study's aim was to determine the associations of HIV and iron status with gut microbiota composition, gut inflammation and gut integrity in South African school-age children. METHODS In this two-way factorial case-control study, 8- to 13-year-old children were enrolled into four groups based on their HIV and iron status: (1) With HIV (HIV+) and ID (n = 43), (2) HIV+ and iron-sufficient nonanaemic (n = 41), (3) without HIV (HIV-) and ID (n = 44) and (4) HIV- and iron-sufficient nonanaemic (n = 38). HIV+ children were virally suppressed (<50 HIV RNA copies/ml) on antiretroviral therapy (ART). Microbial composition of faecal samples (16S rRNA sequencing) and markers of gut inflammation (faecal calprotectin) and gut integrity (plasma intestinal fatty acid-binding protein [I-FABP]) were assessed. RESULTS Faecal calprotectin was higher in ID versus iron-sufficient nonanaemic children (p = 0.007). I-FABP did not significantly differ by HIV or iron status. ART-treated HIV (redundancy analysis [RDA] R2 = 0.009, p = 0.029) and age (RDA R2 = 0.013 p = 0.004) explained the variance in the gut microbiota across the four groups. Probabilistic models showed that the relative abundance of the butyrate-producing genera Anaerostipes and Anaerotruncus was lower in ID versus iron-sufficient children. Fusicatenibacter was lower in HIV+ and in ID children versus their respective counterparts. The prevalence of the inflammation-associated genus Megamonas was 42% higher in children with both HIV and ID versus HIV- and iron-sufficient nonanaemic counterparts. CONCLUSIONS In our sample of 8- to 13-year-old virally suppressed HIV+ and HIV- children with or without ID, ID was associated with increased gut inflammation and changes in the relative abundance of specific microbiota. Moreover, in HIV+ children, ID had a cumulative effect that further shifted the gut microbiota to an unfavourable composition.
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Affiliation(s)
- Charlene Goosen
- Division of Human Nutrition, Department of Global Health, Faculty of Medicine and Health SciencesStellenbosch UniversityCape TownSouth Africa
| | - Sebastian Proost
- Laboratory of Molecular Bacteriology, Department of Microbiology and ImmunologyRega Institute, KU LeuvenLeuvenBelgium
- Center for Microbiology, VIBLeuvenBelgium
| | - Jeannine Baumgartner
- Laboratory of Human Nutrition, Department of Health Sciences and TechnologyETH ZurichZurichSwitzerland
- Department of Nutritional SciencesKing's College LondonLondonUK
| | - Kashish Mallick
- Laboratory of Human Nutrition, Department of Health Sciences and TechnologyETH ZurichZurichSwitzerland
| | - Raul Y. Tito
- Laboratory of Molecular Bacteriology, Department of Microbiology and ImmunologyRega Institute, KU LeuvenLeuvenBelgium
- Center for Microbiology, VIBLeuvenBelgium
| | - Shaun L. Barnabas
- Department of Paediatrics and Child Health, Family Centre for Research with UbuntuStellenbosch UniversityCape TownSouth Africa
| | - Mark F. Cotton
- Department of Paediatrics and Child Health, Family Centre for Research with UbuntuStellenbosch UniversityCape TownSouth Africa
| | - Michael B. Zimmermann
- Laboratory of Human Nutrition, Department of Health Sciences and TechnologyETH ZurichZurichSwitzerland
| | - Jeroen Raes
- Laboratory of Molecular Bacteriology, Department of Microbiology and ImmunologyRega Institute, KU LeuvenLeuvenBelgium
- Center for Microbiology, VIBLeuvenBelgium
| | - Renée Blaauw
- Division of Human Nutrition, Department of Global Health, Faculty of Medicine and Health SciencesStellenbosch UniversityCape TownSouth Africa
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Fu X, Cheng D, Luo Z, Heath SL, Adekunle R, McKinnon JE, Martin L, Sheng Z, Espinosa E, Jiang W. Impacts of plasma microbial lipopolysaccharide translocation on B cell perturbations and anti-CD4 autoantibody production in people with HIV on suppressive antiretroviral therapy. Cell Biosci 2023; 13:78. [PMID: 37138358 PMCID: PMC10157945 DOI: 10.1186/s13578-023-01022-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2022] [Accepted: 03/27/2023] [Indexed: 05/05/2023] Open
Abstract
BACKGROUND . Up to 20% of people with HIV (PWH) who undergo virologically suppressed antiretroviral therapy (ART) fail to experience complete immune restoration. We recently reported that plasma anti-CD4 IgG (antiCD4IgG) autoantibodies from immune non-responders specifically deplete CD4 + T cells via antibody-dependent cytotoxicity. However, the mechanism of antiCD4IgG production remains unclear. METHODS . Blood samples were collected from 16 healthy individuals and 25 PWH on suppressive ART. IgG subclass, plasma lipopolysaccharide (LPS), and antiCD4IgG levels were measured by ELISA. Gene profiles in B cells were analyzed by microarray and quantitative PCR. Furthermore, a patient-derived antiCD4IgG-producing B cell line was generated and stimulated with LPS in vitro. B cell IgG class switch recombination (CSR) was evaluated in response to LPS in splenic B cells from C57/B6 mice in vitro. RESULTS . Increased plasma anti-CD4 IgGs in PWH were predominantly IgG1 and associated with increased plasma LPS levels as well as B cell expression of TLR2, TLR4, and MyD88 mRNA in vivo. Furthermore, LPS stimulation induced antiCD4IgG production in the antiCD4IgG B cell line in vitro. Finally, LPS promoted CSR in vitro. CONCLUSION . Our findings suggest that persistent LPS translocation may promote anti-CD4 autoreactive B cell activation and antiCD4IgG production in PWH on ART, which may contribute to gradual CD4 + T cell depletion. This study suggests that reversing a compromised mucosal barrier could improve ART outcomes in PWH who fail to experience complete immune restoration.
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Affiliation(s)
- Xiaoyu Fu
- Department of Microbiology and Immunology, Medical University of South Carolina, 173 Ashley Ave. BSB207, Charleston, SC, 29425, USA
| | - Da Cheng
- Department of Microbiology and Immunology, Medical University of South Carolina, 173 Ashley Ave. BSB207, Charleston, SC, 29425, USA
| | - Zhenwu Luo
- Department of Microbiology and Immunology, Medical University of South Carolina, 173 Ashley Ave. BSB207, Charleston, SC, 29425, USA
| | - Sonya L Heath
- Department of Medicine, Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, AL, 35294, USA
| | - Ruth Adekunle
- Division of Infectious Diseases, Department of Medicine, Medical University of South Carolina, 173 Ashley Ave. BSB207, Charleston, SC, 29425, USA
- Ralph H. Johnson VA Medical Center, Charleston, SC, 29401, USA
| | - John E McKinnon
- Ralph H. Johnson VA Medical Center, Charleston, SC, 29401, USA
| | - Lisa Martin
- Ralph H. Johnson VA Medical Center, Charleston, SC, 29401, USA
| | - Zizhang Sheng
- Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, 10032, USA
| | - Enrique Espinosa
- Laboratory of Integrative Immunology, National Institute of Respiratory Diseases "Ismael Cosío Villegas", Mexico City, 14080, Mexico
| | - Wei Jiang
- Department of Microbiology and Immunology, Medical University of South Carolina, 173 Ashley Ave. BSB207, Charleston, SC, 29425, USA.
- Division of Infectious Diseases, Department of Medicine, Medical University of South Carolina, 173 Ashley Ave. BSB207, Charleston, SC, 29425, USA.
- Ralph H. Johnson VA Medical Center, Charleston, SC, 29401, USA.
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Powell AM, Persaud D, Anderson JR, Kacanek D, Huo Y, Psoter K, Yanek LR, Ghanem K, Burd I. Markers of intestinal immune activation and inflammation are not associated with preterm birth among women with low level HIV viremia. Am J Reprod Immunol 2023; 89:e13680. [PMID: 36680487 PMCID: PMC10026076 DOI: 10.1111/aji.13680] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 12/30/2022] [Accepted: 01/10/2023] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND Maternal markers of intestinal immune activation may be used to predict preterm birth (PTB) in pregnant women living with HIV. METHODS This study used de-identified samples from the International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT) Protocol P1025 study. Singleton pregnancies with ≥3 ml plasma available and HIV viral load ≤400 copies/ml within 4 weeks of specimen collection were included. Frequency matching of PTB cases and term birth controls was performed on basis of maternal race, number of available plasma specimens, and timing of plasma sample collection in a 1:1 ratio. Plasma progesterone, 25-hydroxy vitamin D, soluble CD14, intestinal fatty acid binding protein (I-FABP), Lipopolysaccharide (LPS)-binding protein, and inflammatory cytokines (IL-1B, IFN-gamma, IL-6, TNF-alpha) were measured. Generalized mixed linear regression modeling was used to examine the association between PTB and biomarkers, adjusting for covariates and confounders. Data analyses were performed using SAS 9.4 (Cary, NC). RESULTS We included 104 PTB compared to 104 controls. Third trimester log2 IL-1B was lower among PTB versus term birth controls by univariate analysis (-1.50 ± 2.26 vs. -.24 ± 2.69, p = .01) though this association was no longer significant by regression modeling. In an uncontrolled, exploratory sub-analysis, subjects with prior PTB had increased odds of PTB with higher I-FABP [aOR 2.72, 95% CI 1.18-6.24] and lower IFN-gamma [aOR .23, 95% CI .12-.41] after adjustment for covariates and confounders. CONCLUSIONS Intestinal immune activation measured by soluble CD14 or intestinal fatty acid binding protein was not associated with preterm birth among pregnant women with low-level HIV viremia.
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Affiliation(s)
- Anna Maya Powell
- Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Deborah Persaud
- Department of Pediatrics, Division of Pediatric Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Jean Rene Anderson
- Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Deborah Kacanek
- Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
| | - Yanling Huo
- Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
| | - Kevin Psoter
- BEADCore, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Lisa R Yanek
- BEADCore, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Khalil Ghanem
- Department of Medicine, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Irina Burd
- Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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Cheng D, Luo Z, Fitting S, Stoops W, Heath SL, Ndhlovu LC, Jiang W. The link between chronic cocaine use, B cell perturbations, and blunted immune recovery in HIV-infected individuals on suppressive ART. NEUROIMMUNE PHARMACOLOGY AND THERAPEUTICS 2023; 2:71-79. [PMID: 37027536 PMCID: PMC10070012 DOI: 10.1515/nipt-2022-0019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Accepted: 01/27/2023] [Indexed: 06/04/2023]
Abstract
Background We recently reveal that anti-CD4 autoantibodies contribute to blunted CD4+ T cell reconstitution in HIV+ individuals on antiretroviral therapy (ART). Cocaine use is common among HIV+ individuals and is associated with accelerated disease progression. However, the mechanisms underlying cocaine-induced immune perturbations remain obscure. Methods We evaluated plasma levels of anti-CD4 IgG and markers of microbial translocation, as well as B-cell gene expression profiles and activation in HIV+ chronic cocaine users and non-users on suppressive ART, as well as uninfected controls. Plasma purified anti-CD4 IgGs were assessed for antibody-dependent cytotoxicity (ADCC). Results HIV+ cocaine users had increased plasma levels of anti-CD4 IgGs, lipopolysaccharide (LPS), and soluble CD14 (sCD14) versus non-users. An inverse correlation was observed in cocaine users, but not non-drug users. Anti-CD4 IgGs from HIV+ cocaine users mediated CD4+ T cell death through ADCC in vitro. B cells from HIV+ cocaine users exhibited activation signaling pathways and activation (cycling and TLR4 expression) related to microbial translocation versus non-users. Conclusions This study improves our understanding of cocaine associated B cell perturbations and immune failure and the new appreciation for autoreactive B cells as novel therapeutic targets.
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Affiliation(s)
- Da Cheng
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA
| | - Zhenwu Luo
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA
| | - Sylvia Fitting
- Department of Psychology & Neuroscience, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - William Stoops
- Department of Behavioral Science, Department of Psychiatry, Center on Drug and Alcohol Research, Department of Psychology, University of Kentucky College of Medicine and College of Arts and Sciences, Lexington, KY, USA
| | - Sonya L. Heath
- Department of Medicine, Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Lishomwa C. Ndhlovu
- Department of Medicine, Division of Infectious Diseases, Weill Cornell Medicine, New York, NY, USA
| | - Wei Jiang
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA
- Ralph H. Johnson VA Medical Center, Charleston, SC, USA
- Divison of Infectious Diseases, Department of Medicine, Medical University of South Carolina, Charleston, USA
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Ullah Goraya M, Li R, Gu L, Deng H, Wang G. Blood Stream Microbiota Dysbiosis Establishing New Research Standards in Cardio-Metabolic Diseases, A Meta-Analysis Study. Microorganisms 2023; 11:microorganisms11030777. [PMID: 36985350 PMCID: PMC10052040 DOI: 10.3390/microorganisms11030777] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 03/09/2023] [Accepted: 03/11/2023] [Indexed: 03/19/2023] Open
Abstract
AIMS Scientists have recently discovered a link between the circulating microbiome and homeostasis, as well as the pathogenesis of a number of metabolic diseases. It has been demonstrated that low-grade chronic inflammation is one of the primary mechanisms that has long been implicated in the risk of cardio-metabolic disease (CMDs) and its progression. Currently, the dysbiosis of circulating bacteria is considered as a key regulator for chronic inflammation in CMDs, which is why we have conducted this systemic review focused on circulating bacterial dysbiosis. METHODS A systemic review of clinical and research-based studies was conducted via PubMed, Scopus, Medline, and Web of Science. Literature was considered for risk of bias and patterns of intervention effects. A randomized effect model was used to evaluate the dysbiosis of circulating microbiota and clinical outcomes. We conducted a meta-analysis considering the circulating bacteria in both healthy people and people with cardio-metabolic disorders, in reports published mainly from 2008 to 2022, according to the PRISMA guidelines. RESULTS We searched 627 studies and, after completing the risk of bias and selection, 31 studies comprising of 11,132 human samples were considered. This meta-analysis found that dysbiosis of phyla Proteobacteria, Firmicutes, and Bacteroidetes was associated with metabolic diseases. CONCLUSIONS In most instances, metabolic diseases are linked to higher diversity and elevated bacterial DNA levels. Bacteroides abundance was higher in healthy people than with metabolic disorders. However, more rigorous studies are required to determine the role of bacterial dysbiosis in cardio-metabolic diseases. Understanding the relationship between dysbiosis and cardio-metabolic diseases, we can use the bacteria as therapeutics for the reversal of dysbiosis and targets for therapeutics use in cardio-metabolic diseases. In the future, circulating bacterial signatures can be used as biomarkers for the early detection of metabolic diseases.
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Affiliation(s)
| | - Rui Li
- Correspondence: (R.L.); (G.W.)
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20
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Cheng HS, Tan SP, Wong DMK, Koo WLY, Wong SH, Tan NS. The Blood Microbiome and Health: Current Evidence, Controversies, and Challenges. Int J Mol Sci 2023; 24:5633. [PMID: 36982702 PMCID: PMC10059777 DOI: 10.3390/ijms24065633] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Revised: 03/14/2023] [Accepted: 03/14/2023] [Indexed: 03/18/2023] Open
Abstract
Blood is conventionally thought to be sterile. However, emerging evidence on the blood microbiome has started to challenge this notion. Recent reports have revealed the presence of genetic materials of microbes or pathogens in the blood circulation, leading to the conceptualization of a blood microbiome that is vital for physical wellbeing. Dysbiosis of the blood microbial profile has been implicated in a wide range of health conditions. Our review aims to consolidate recent findings about the blood microbiome in human health and to highlight the existing controversies, prospects, and challenges around this topic. Current evidence does not seem to support the presence of a core healthy blood microbiome. Common microbial taxa have been identified in some diseases, for instance, Legionella and Devosia in kidney impairment, Bacteroides in cirrhosis, Escherichia/Shigella and Staphylococcus in inflammatory diseases, and Janthinobacterium in mood disorders. While the presence of culturable blood microbes remains debatable, their genetic materials in the blood could potentially be exploited to improve precision medicine for cancers, pregnancy-related complications, and asthma by augmenting patient stratification. Key controversies in blood microbiome research are the susceptibility of low-biomass samples to exogenous contamination and undetermined microbial viability from NGS-based microbial profiling, however, ongoing initiatives are attempting to mitigate these issues. We also envisage future blood microbiome research to adopt more robust and standardized approaches, to delve into the origins of these multibiome genetic materials and to focus on host-microbe interactions through the elaboration of causative and mechanistic relationships with the aid of more accurate and powerful analytical tools.
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Affiliation(s)
- Hong Sheng Cheng
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore 308232, Singapore; (S.H.W.); (N.S.T.)
| | - Sin Pei Tan
- Radiotherapy and Oncology Department, Hospital Sultan Ismail, Jalan Mutiara Emas Utama, Taman Mount Austin, Johor Bahru 81100, Malaysia
| | - David Meng Kit Wong
- School of Biological Sciences, Nanyang Technological University Singapore, Singapore 637551, Singapore
| | - Wei Ling Yolanda Koo
- School of Biological Sciences, Nanyang Technological University Singapore, Singapore 637551, Singapore
| | - Sunny Hei Wong
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore 308232, Singapore; (S.H.W.); (N.S.T.)
| | - Nguan Soon Tan
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore 308232, Singapore; (S.H.W.); (N.S.T.)
- School of Biological Sciences, Nanyang Technological University Singapore, Singapore 637551, Singapore
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21
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Hileman CO, Durieux JC, Janus SE, Bowman E, Kettelhut A, Nguyen TT, Avery AK, Funderburg N, Sullivan C, McComsey GA. Heroin Use Is Associated With Vascular Inflammation in Human Immunodeficiency Virus. Clin Infect Dis 2023; 76:375-381. [PMID: 36208157 PMCID: PMC10169434 DOI: 10.1093/cid/ciac812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 09/27/2022] [Accepted: 10/05/2022] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Heroin use may work synergistically with human immunodeficiency virus (HIV) infection to cause greater immune dysregulation than either factor alone. Unraveling how this affects end-organ disease is key as it may play a role in the excess mortality seen in people with HIV (PWH) who use heroin despite access to care and antiretroviral therapy. METHODS This is a prospectively enrolled, cross-sectional study of adults with and without HIV who use and do not use heroin using (18)F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) to compare tissue-specific inflammation including aortic (target-to-background ratio [TBR]), splenic, and bone marrow (standardized uptake value [SUV]). RESULTS A total of 120 participants were enrolled. The unadjusted mean difference in aortic TBR was 0.43 between HIV-positive [HIV+] heroin+ and HIV+ heroin-negative [heroin-] (P = .02); however, among HIV-, aortic TBR was similar regardless of heroin-use status. Further, HIV-by-heroin-use status interaction was significant (P = .02), indicating that the relationship between heroin use and higher aortic TBR depended on HIV status. On the other hand, both HIV (1.54 vs 1.68; P = .04, unadjusted estimated means for HIV+ vs HIV-) and heroin use were associated with lower bone marrow SUV, although the effect of heroin depended on sex (heroin-use-by-sex interaction, P = .03). HIV-by-heroin-use interaction was not significant for splenic or bone marrow SUV. CONCLUSIONS Aortic inflammation was greatest in PWH who use heroin, but paradoxically, bone marrow activity was the least in this group, suggesting complex and possibly divergent pathophysiology within these different end organs.
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Affiliation(s)
- Corrilynn O Hileman
- Department of Medicine, Division of Infectious Disease, MetroHealth Medical Center, Cleveland, Ohio, USA
- School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA
| | - Jared C Durieux
- Department of Medicine and Pediatrics, Division of Infectious Disease, University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA
| | - Scott E Janus
- Harrington Heart and Vascular Institute, University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA
| | - Emily Bowman
- School of Health and Rehabilitation Sciences, Division of Medical Laboratory Science, The Ohio State University, Columbus, Ohio, USA
| | - Aaren Kettelhut
- School of Health and Rehabilitation Sciences, Division of Medical Laboratory Science, The Ohio State University, Columbus, Ohio, USA
| | - Trong-Tuong Nguyen
- Department of Medicine, Division of Infectious Disease, MetroHealth Medical Center, Cleveland, Ohio, USA
| | - Ann K Avery
- Department of Medicine, Division of Infectious Disease, MetroHealth Medical Center, Cleveland, Ohio, USA
- School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA
| | - Nicholas Funderburg
- School of Health and Rehabilitation Sciences, Division of Medical Laboratory Science, The Ohio State University, Columbus, Ohio, USA
| | - Claire Sullivan
- School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA
- Harrington Heart and Vascular Institute, University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA
| | - Grace A McComsey
- School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA
- Department of Medicine and Pediatrics, Division of Infectious Disease, University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA
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22
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Yan L, Xu K, Xiao Q, Tuo L, Luo T, Wang S, Yang R, Zhang F, Yang X. Cellular and molecular insights into incomplete immune recovery in HIV/AIDS patients. Front Immunol 2023; 14:1152951. [PMID: 37205108 PMCID: PMC10185893 DOI: 10.3389/fimmu.2023.1152951] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Accepted: 04/18/2023] [Indexed: 05/21/2023] Open
Abstract
Highly active antiretroviral therapy (ART) can effectively inhibit virus replication and restore immune function in most people living with human immunodeficiency virus (HIV). However, an important proportion of patients fail to achieve a satisfactory increase in CD4+ T cell counts. This state is called incomplete immune reconstitution or immunological nonresponse (INR). Patients with INR have an increased risk of clinical progression and higher rates of mortality. Despite widespread attention to INR, the precise mechanisms remain unclear. In this review, we will discuss the alterations in the quantity and quality of CD4+ T as well as multiple immunocytes, changes in soluble molecules and cytokines, and their relationship with INR, aimed to provide cellular and molecular insights into incomplete immune reconstitution.
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Affiliation(s)
- Liting Yan
- Department of Infectious Disease, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
- *Correspondence: Xingxiang Yang, ; Fujie Zhang, ; Liting Yan,
| | - Kaiju Xu
- Department of Infectious Disease, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Qing Xiao
- Clinical and Research Center for Infectious Diseases, Beijing Ditan Hospital, Beijing, China
| | - Lin Tuo
- Department of Infectious Disease, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Tingting Luo
- Department of Infectious Disease, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Shuqiang Wang
- Department of Infectious Disease, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Renguo Yang
- Department of Infectious Disease, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Fujie Zhang
- Clinical and Research Center for Infectious Diseases, Beijing Ditan Hospital, Beijing, China
- *Correspondence: Xingxiang Yang, ; Fujie Zhang, ; Liting Yan,
| | - Xingxiang Yang
- Department of Infectious Disease, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
- *Correspondence: Xingxiang Yang, ; Fujie Zhang, ; Liting Yan,
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23
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Cuesta-Sancho S, Márquez-Ruiz D, Illanes-Álvarez F, Campaña-Gómez I, Martín-Aspas A, Trujillo-Soto MT, Romero A, Galán F, Rodríguez-Iglesias M, Márquez-Coello M, Girón-González JA. Expression profile of microRNAs related with viral infectivity, inflammatory response, and immune activation in people living with HIV. Front Microbiol 2023; 14:1136718. [PMID: 36937285 PMCID: PMC10017538 DOI: 10.3389/fmicb.2023.1136718] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Accepted: 02/10/2023] [Indexed: 03/06/2023] Open
Abstract
Objective To evaluate the serum expression of microRNAs (miRNAs) with ability to modulate the human immunodeficiency (HIV) replication or inflammatory status in people living with HIV (PLWH). Methods Forty healthy controls and two groups of PLWH were evaluated: (a) Group 1 (n = 30), patients with detectable viral load at inclusion, analyzed before receiving antiretroviral therapy (ART) and 12 months after initiating it; (b) Group 2 (n = 55), PLWH with prolonged undetectable viral load. Intestinal barrier disruption (I-FABP) and bacterial translocation (16S rDNA) markers, inflammatory markers such as interleukin (IL)-6 and sCD163, immune activation and expression of specific miRNAs were evaluated. Results Serum concentrations of I-FABP, 16S rDNA, IL-6, sCD163 and activated T lymphocytes were increased in PLWH. Serum miR-34a was overexpressed at inclusion and remained elevated after ART. The expression of the remaining miRNAs that modulate HIV infectivity (miR-7, mir-29a, miR-150, and miR-223) was similar in PLWH and controls. Related to miRNAs implicated in inflammation (miR-21, miR-155, and miR-210), significant overexpression were observed in miR-21 and miR-210 levels in untreated PLWH, but levels were restored in those patients treated for a long period. Conclusion A sustained overexpression of miR-34a was detected even after prolonged HIV controlled replication. miR-21 and miR-210 can be considered new markers of inflammation with high sensitivity to its modifications.
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Affiliation(s)
- Sara Cuesta-Sancho
- Unidad de Enfermedades Infecciosas, Servicio de Medicina Interna, Facultad de Medicina, Hospital Universitario Puerta del Mar, Instituto de Investigación e Innovación en Ciencias Biomédicas de Cádiz (INiBICA), Universidad de Cádiz, Cádiz, Spain
| | - Denisse Márquez-Ruiz
- Unidad de Enfermedades Infecciosas, Servicio de Medicina Interna, Facultad de Medicina, Hospital Universitario Puerta del Mar, Instituto de Investigación e Innovación en Ciencias Biomédicas de Cádiz (INiBICA), Universidad de Cádiz, Cádiz, Spain
| | - Francisco Illanes-Álvarez
- Unidad de Enfermedades Infecciosas, Servicio de Medicina Interna, Facultad de Medicina, Hospital Universitario Puerta del Mar, Instituto de Investigación e Innovación en Ciencias Biomédicas de Cádiz (INiBICA), Universidad de Cádiz, Cádiz, Spain
| | - Irene Campaña-Gómez
- Unidad de Enfermedades Infecciosas, Servicio de Medicina Interna, Facultad de Medicina, Hospital Universitario Puerta del Mar, Instituto de Investigación e Innovación en Ciencias Biomédicas de Cádiz (INiBICA), Universidad de Cádiz, Cádiz, Spain
| | - Andrés Martín-Aspas
- Unidad de Enfermedades Infecciosas, Servicio de Medicina Interna, Facultad de Medicina, Hospital Universitario Puerta del Mar, Instituto de Investigación e Innovación en Ciencias Biomédicas de Cádiz (INiBICA), Universidad de Cádiz, Cádiz, Spain
| | - María Teresa Trujillo-Soto
- Servicio de Microbiología, Facultad de Medicina, Hospital Universitario Puerta del Mar, Instituto de Investigación e Innovación en Ciencias Biomédicas de Cádiz (INiBICA), Universidad de Cádiz, Cádiz, Spain
| | - Alberto Romero
- Unidad de Enfermedades Infecciosas, Facultad de Medicina, Hospital Universitario Puerto Real, Instituto de Investigación e Innovación en Ciencias Biomédicas de Cádiz (INiBICA), Universidad de Cádiz, Cádiz, Spain
| | - Fátima Galán
- Servicio de Microbiología, Facultad de Medicina, Hospital Universitario Puerta del Mar, Instituto de Investigación e Innovación en Ciencias Biomédicas de Cádiz (INiBICA), Universidad de Cádiz, Cádiz, Spain
| | - Manuel Rodríguez-Iglesias
- Servicio de Microbiología, Facultad de Medicina, Hospital Universitario Puerta del Mar, Instituto de Investigación e Innovación en Ciencias Biomédicas de Cádiz (INiBICA), Universidad de Cádiz, Cádiz, Spain
| | - Mercedes Márquez-Coello
- Unidad de Enfermedades Infecciosas, Servicio de Medicina Interna, Facultad de Medicina, Hospital Universitario Puerta del Mar, Instituto de Investigación e Innovación en Ciencias Biomédicas de Cádiz (INiBICA), Universidad de Cádiz, Cádiz, Spain
| | - José-Antonio Girón-González
- Unidad de Enfermedades Infecciosas, Servicio de Medicina Interna, Facultad de Medicina, Hospital Universitario Puerta del Mar, Instituto de Investigación e Innovación en Ciencias Biomédicas de Cádiz (INiBICA), Universidad de Cádiz, Cádiz, Spain
- *Correspondence: José-Antonio Girón-González,
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24
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Ouyang J, Yan J, Zhou X, Isnard S, Harypursat V, Cui H, Routy JP, Chen Y. Relevance of biomarkers indicating gut damage and microbial translocation in people living with HIV. Front Immunol 2023; 14:1173956. [PMID: 37153621 PMCID: PMC10160480 DOI: 10.3389/fimmu.2023.1173956] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Accepted: 04/10/2023] [Indexed: 05/10/2023] Open
Abstract
The intestinal barrier has the daunting task of allowing nutrient absorption while limiting the entry of microbial products into the systemic circulation. HIV infection disrupts the intestinal barrier and increases intestinal permeability, leading to microbial product translocation. Convergent evidence has shown that gut damage and an enhanced level of microbial translocation contribute to the enhanced immune activation, the risk of non-AIDS comorbidity, and mortality in people living with HIV (PLWH). Gut biopsy procedures are invasive, and are not appropriate or feasible in large populations, even though they are the gold standard for intestinal barrier investigation. Thus, validated biomarkers that measure the degree of intestinal barrier damage and microbial translocation are needed in PLWH. Hematological biomarkers represent an objective indication of specific medical conditions and/or their severity, and should be able to be measured accurately and reproducibly via easily available and standardized blood tests. Several plasma biomarkers of intestinal damage, i.e., intestinal fatty acid-binding protein (I-FABP), zonulin, and regenerating islet-derived protein-3α (REG3α), and biomarkers of microbial translocation, such as lipopolysaccharide (LPS) and (1,3)-β-D-Glucan (BDG) have been used as markers of risk for developing non-AIDS comorbidities in cross sectional analyses and clinical trials, including those aiming at repair of gut damage. In this review, we critically discuss the value of different biomarkers for the estimation of gut permeability levels, paving the way towards developing validated diagnostic and therapeutic strategies to repair gut epithelial damage and to improve overall disease outcomes in PLWH.
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Affiliation(s)
- Jing Ouyang
- Department of Infectious Diseases, Chongqing Public Health Medical Center, Chongqing, China
- Clinical Research Center, Chongqing Public Health Medical Center, Chongqing, China
| | - Jiangyu Yan
- Department of Infectious Diseases, Chongqing Public Health Medical Center, Chongqing, China
- Clinical Research Center, Chongqing Public Health Medical Center, Chongqing, China
| | - Xin Zhou
- Clinical Research Center, Chongqing Public Health Medical Center, Chongqing, China
- Cancer Center, Medical Research Institute, Southwest University, Chongqing, China
| | - Stéphane Isnard
- Infectious Diseases and Immunity in Global Health Program, Research Institute, McGill University Health Centre, Montréal, QC, Canada
- Chronic Viral Illness Service, McGill University Health Centre, Montréal, QC, Canada
- Canadian HIV Trials Network, Canadian Institutes for Health Research, Vancouver, BC, Canada
| | - Vijay Harypursat
- Department of Infectious Diseases, Chongqing Public Health Medical Center, Chongqing, China
- Clinical Research Center, Chongqing Public Health Medical Center, Chongqing, China
| | - Hongjuan Cui
- Cancer Center, Medical Research Institute, Southwest University, Chongqing, China
| | - Jean-Pierre Routy
- Infectious Diseases and Immunity in Global Health Program, Research Institute, McGill University Health Centre, Montréal, QC, Canada
- Chronic Viral Illness Service, McGill University Health Centre, Montréal, QC, Canada
- Division of Hematology, McGill University Health Centre, Montréal, QC, Canada
- *Correspondence: Jean-Pierre Routy, ; Yaokai Chen,
| | - Yaokai Chen
- Department of Infectious Diseases, Chongqing Public Health Medical Center, Chongqing, China
- *Correspondence: Jean-Pierre Routy, ; Yaokai Chen,
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25
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Zaongo SD, Ouyang J, Isnard S, Zhou X, Harypursat V, Cui H, Routy JP, Chen Y. Candida albicans can foster gut dysbiosis and systemic inflammation during HIV infection. Gut Microbes 2023; 15:2167171. [PMID: 36722096 PMCID: PMC9897780 DOI: 10.1080/19490976.2023.2167171] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
Candida albicans (C. albicans) is a ubiquitous fungal commensal component of the human microbiota, and under certain circumstances, such as during an immunocompromised state, it may initiate different types of infection. Moreover, C. albicans continuously and reciprocally interacts with the host immune system as well as with other elements of the gut microbiota, thus contributing significantly to both gut homeostasis and host immunity. People living with HIV (PLWH), including those receiving antiretroviral therapy, are characterized by a depletion of CD4 + T-cells and dysbiosis in their gut. C. albicans colonization is frequent in PLWH, causing both a high prevalence and high morbidity. Gut barrier damage and elevated levels of microbial translocation are also fairly common in this population. Herein, we take a closer look at the reciprocity among C. albicans, gut microbiota, HIV, and the host immune system, thus throwing some light on this complex interplay.
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Affiliation(s)
- Silvere D Zaongo
- Department of Infectious Diseases, Chongqing Public Health Medical Center, Chongqing, China,Clinical Research Center, Chongqing Public Health Medical Center, Chongqing, China
| | - Jing Ouyang
- Clinical Research Center, Chongqing Public Health Medical Center, Chongqing, China
| | - Stéphane Isnard
- Infectious Diseases and Immunity in Global Health Program, Research Institute, McGill University Health Centre, Montréal, QC, Canada,Chronic Viral Illness Service, McGill University Health Centre, Montréal, QC, Canada,Canadian HIV Trials Network, Canadian Institutes for Health Research, Vancouver, British Columbia, Canada
| | - Xin Zhou
- Clinical Research Center, Chongqing Public Health Medical Center, Chongqing, China,Cancer Center, Medical Research Institute, Southwest University, Chongqing, China
| | - Vijay Harypursat
- Clinical Research Center, Chongqing Public Health Medical Center, Chongqing, China
| | - Hongjuan Cui
- Cancer Center, Medical Research Institute, Southwest University, Chongqing, China
| | - Jean-Pierre Routy
- Infectious Diseases and Immunity in Global Health Program, Research Institute, McGill University Health Centre, Montréal, QC, Canada,Chronic Viral Illness Service, McGill University Health Centre, Montréal, QC, Canada,Division of Hematology, McGill University Health Centre, Montréal, QC, Canada
| | - Yaokai Chen
- Department of Infectious Diseases, Chongqing Public Health Medical Center, Chongqing, China,Clinical Research Center, Chongqing Public Health Medical Center, Chongqing, China,CONTACT Yaokai Chen Department of Infectious Diseases, Chongqing Public Health Medical Center, Chongqing, China
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26
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Fulcher JA, Li F, Tobin NH, Zabih S, Elliott J, Clark JL, D'Aquila R, Mustanski B, Kipke MD, Shoptaw S, Gorbach PM, Aldrovandi GM. Gut dysbiosis and inflammatory blood markers precede HIV with limited changes after early seroconversion. EBioMedicine 2022; 84:104286. [PMID: 36179550 PMCID: PMC9520213 DOI: 10.1016/j.ebiom.2022.104286] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Revised: 09/07/2022] [Accepted: 09/09/2022] [Indexed: 11/07/2022] Open
Abstract
BACKGROUND Alterations in the gut microbiome have been associated with HIV infection, but the relative impact of HIV versus other factors on the gut microbiome has been difficult to determine in cross-sectional studies. METHODS To address this, we examined the gut microbiome, serum metabolome, and cytokines longitudinally within 27 individuals before and during acute HIV using samples collected from several ongoing cohort studies. Matched control participants (n=28) from the same cohort studies without HIV but at similar behavioral risk were used for comparison. FINDINGS We identified few changes in the microbiome during acute HIV infection, but did find alterations in serum metabolites involving secondary bile acid (lithocholate sulfate, glycocholenate sulfate) and amino acid metabolism (3-methyl-2-oxovalerate, serine, cysteine, N-acetylputrescine). Greater microbiome differences, including decreased Bacteroides spp and increased Megasphaera elsdenii, were seen when comparing pre-HIV infection visits to matched at-risk controls. Those who acquired HIV also had elevated inflammatory cytokines (TNF-α, B cell activating factor, IL-8) and bioactive lipids (palmitoyl-sphingosine-phosphoethanolamide and glycerophosphoinositol) prior to HIV acquisition compared to matched controls. INTERPRETATION Longitudinal sampling identified pre-existing microbiome differences in participants with acute HIV compared to matched control participants observed over the same period. These data highlight the importance of increasing understanding of the role of the microbiome in HIV susceptibility. FUNDING This work was supported by NIH/NIAID (K08AI124979; P30AI117943), NIH/NIDA (U01DA036267; U01DA036939; U01DA036926; U24DA044554), and NIH/NIMH (P30MH058107; R34MH105272).
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Affiliation(s)
- Jennifer A Fulcher
- Division of Infectious Diseases, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA; VA Greater Los Angeles Healthcare System, Los Angeles, CA 90073, USA.
| | - Fan Li
- Division of Infectious Diseases, Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
| | - Nicole H Tobin
- Division of Infectious Diseases, Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
| | - Sara Zabih
- Division of Infectious Diseases, Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
| | - Julie Elliott
- Division of Infectious Diseases, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
| | - Jesse L Clark
- Division of Infectious Diseases, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
| | - Richard D'Aquila
- Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Brian Mustanski
- Department of Medical Social Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Institute for Sexual and Gender Minority Health and Wellbeing, Northwestern University, Chicago, IL 60611, USA
| | - Michele D Kipke
- Children's Hospital Los Angeles, Los Angeles, CA 90027, USA; Department of Pediatrics, Keck School of Medicine at the University of Southern California, Los Angeles, CA 90027, USA
| | - Steven Shoptaw
- Department of Family Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
| | - Pamina M Gorbach
- Department of Epidemiology, Fielding School of Public Health, University of California Los Angeles, Los Angeles, CA 90095, USA
| | - Grace M Aldrovandi
- Division of Infectious Diseases, Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
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Byrnes SJ, Angelovich TA, Busman-Sahay K, Cochrane CR, Roche M, Estes JD, Churchill MJ. Non-Human Primate Models of HIV Brain Infection and Cognitive Disorders. Viruses 2022; 14:v14091997. [PMID: 36146803 PMCID: PMC9500831 DOI: 10.3390/v14091997] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Revised: 09/03/2022] [Accepted: 09/07/2022] [Indexed: 11/17/2022] Open
Abstract
Human Immunodeficiency virus (HIV)-associated neurocognitive disorders are a major burden for people living with HIV whose viremia is stably suppressed with antiretroviral therapy. The pathogenesis of disease is likely multifaceted, with contributions from viral reservoirs including the brain, chronic and systemic inflammation, and traditional risk factors including drug use. Elucidating the effects of each element on disease pathogenesis is near impossible in human clinical or ex vivo studies, facilitating the need for robust and accurate non-human primate models. In this review, we describe the major non-human primate models of neuroHIV infection, their use to study the acute, chronic, and virally suppressed infection of the brain, and novel therapies targeting brain reservoirs and inflammation.
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Affiliation(s)
- Sarah J. Byrnes
- School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC 3083, Australia
| | - Thomas A. Angelovich
- School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC 3083, Australia
- The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC 3000, Australia
- Life Sciences, Burnet Institute, Melbourne, VIC 3004, Australia
| | - Kathleen Busman-Sahay
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Portland, OR 97006, USA
| | - Catherine R. Cochrane
- School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC 3083, Australia
| | - Michael Roche
- School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC 3083, Australia
- The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC 3000, Australia
| | - Jacob D. Estes
- School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC 3083, Australia
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Portland, OR 97006, USA
- Oregon National Primate Research Centre, Oregon Health & Science University, Portland, OR 97006, USA
| | - Melissa J. Churchill
- School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC 3083, Australia
- Life Sciences, Burnet Institute, Melbourne, VIC 3004, Australia
- Departments of Microbiology and Medicine, Monash University, Clayton, VIC 3800, Australia
- Correspondence:
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Plasma d-amino acids are associated with markers of immune activation and organ dysfunction in people with HIV. AIDS 2022; 36:911-921. [PMID: 35212669 DOI: 10.1097/qad.0000000000003207] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND d-Amino acids (d-AAs) have been associated with age-associated conditions in the general population but their relevance in people with HIV (PWH), who experience accentuated/accelerated aging has not been studied. We compared d-AA levels in HIV-infected and uninfected controls and explored their association with markers of immune activation, gut permeability and organ dysfunction. DESIGN Case-control analysis. METHOD Plasma samples from 60 antiretroviral therapy-treated HIV-infected individuals and 59 uninfected controls were analysed. A three-dimensional HPLC system was used to measure d-and l-asparagine, serine, alanine and proline and presented as %d-AA. Additionally, cell-associated and soluble markers of immune activation and senescence were characterized. Kidney and liver functions were expressed as estimated glomerular filtration rate and fibrosis-4 scores, respectively. Mann-Whitney and Spearman rank correlation coefficients were used for statistical analysis. RESULTS d-Asparagine, d-serine, d-alanine and d-proline were detectable in all plasma samples and correlated with age in HIV-infected and uninfected but not different between groups. Kynurenine/tryptophan ratio was positively correlated with all %d-AAs in PWH and with %d-serine and %d-proline in controls. %d-AAs were not consistently correlated with markers of gut permeability in both groups. All %d-AAs were also correlated with kidney function in both groups whereas age-associated accumulation of %d-asparagine, %d-serine and %d-proline were correlated with liver function and the VACS score in controls. CONCLUSION Plasma d-AAs are associated with chronological age and correlated with markers of immune activation and organ decline, though variably, in PWH and controls. Their role in the biology of aging warrants further investigation.
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Sumida K, Han Z, Chiu CY, Mims TS, Bajwa A, Demmer RT, Datta S, Kovesdy CP, Pierre JF. Circulating Microbiota in Cardiometabolic Disease. Front Cell Infect Microbiol 2022; 12:892232. [PMID: 35592652 PMCID: PMC9110890 DOI: 10.3389/fcimb.2022.892232] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 04/11/2022] [Indexed: 12/14/2022] Open
Abstract
The rapid expansion of microbiota research has significantly advanced our understanding of the complex interactions between gut microbiota and cardiovascular, metabolic, and renal system regulation. Low-grade chronic inflammation has long been implicated as one of the key mechanisms underlying cardiometabolic disease risk and progression, even before the insights provided by gut microbiota research in the past decade. Microbial translocation into the bloodstream can occur via different routes, including through the oral and/or intestinal mucosa, and may contribute to chronic inflammation in cardiometabolic disease. Among several gut-derived products identifiable in the systemic circulation, bacterial endotoxins and metabolites have been extensively studied, however recent advances in microbial DNA sequencing have further allowed us to identify highly diverse communities of microorganisms in the bloodstream from an -omics standpoint, which is termed "circulating microbiota." While detecting microorganisms in the bloodstream was historically considered as an indication of infection, evidence on the circulating microbiota is continually accumulating in various patient populations without clinical signs of infection and even in otherwise healthy individuals. Moreover, both quantitative and compositional alterations of the circulating microbiota have recently been implicated in the pathogenesis of chronic inflammatory conditions, potentially through their immunostimulatory, atherogenic, and cardiotoxic properties. In this mini review, we aim to provide recent evidence on the characteristics and roles of circulating microbiota in several cardiometabolic diseases, such as type 2 diabetes, cardiovascular disease, and chronic kidney disease, with highlights of our emerging findings on circulating microbiota in patients with end-stage kidney disease undergoing hemodialysis.
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Affiliation(s)
- Keiichi Sumida
- Division of Nephrology, Department of Medicine, University of Tennessee Health Science Center, Memphis, TN, United States,*Correspondence: Keiichi Sumida,
| | - Zhongji Han
- Division of Nephrology, Department of Medicine, University of Tennessee Health Science Center, Memphis, TN, United States
| | - Chi-Yang Chiu
- Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, TN, United States
| | - Tahliyah S. Mims
- Department of Nutritional Sciences, College of Agriculture and Life Science, University of Wisconsin-Madison, Madison, WI, United States
| | - Amandeep Bajwa
- Transplant Research Institute, James D. Eason Transplant Institute, Department of Surgery, School of Medicine, University of Tennessee Health Science Center, Memphis, TN, United States
| | - Ryan T. Demmer
- Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, United States,Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, United States
| | - Susmita Datta
- Department of Biostatistics, University of Florida, Gainesville, FL, United States
| | - Csaba P. Kovesdy
- Division of Nephrology, Department of Medicine, University of Tennessee Health Science Center, Memphis, TN, United States,Nephrology Section, Memphis Veterans Affairs (VA) Medical Center, Memphis, TN, United States
| | - Joseph F. Pierre
- Department of Nutritional Sciences, College of Agriculture and Life Science, University of Wisconsin-Madison, Madison, WI, United States
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Ferrari B, Da Silva AC, Liu KH, Saidakova EV, Korolevskaya LB, Shmagel KV, Shive C, Pacheco Sanchez G, Retuerto M, Sharma AA, Ghneim K, Noel-Romas L, Rodriguez B, Ghannoum MA, Hunt PP, Deeks SG, Burgener AD, Jones DP, Dobre MA, Marconi VC, Sekaly RP, Younes SA. Gut-derived bacterial toxins impair memory CD4+ T cell mitochondrial function in HIV-1 infection. J Clin Invest 2022; 132:e149571. [PMID: 35316209 PMCID: PMC9057623 DOI: 10.1172/jci149571] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Accepted: 03/16/2022] [Indexed: 11/17/2022] Open
Abstract
People living with HIV (PLWH) who are immune nonresponders (INRs) are at greater risk of comorbidity and mortality than are immune responders (IRs) who restore their CD4+ T cell count after antiretroviral therapy (ART). INRs have low CD4+ T cell counts (<350 c/μL), heightened systemic inflammation, and increased CD4+ T cell cycling (Ki67+). Here, we report the findings that memory CD4+ T cells and plasma samples of INRs from several cohorts are enriched in gut-derived bacterial solutes p-cresol sulfate (PCS) and indoxyl sulfate (IS) that both negatively correlated with CD4+ T cell counts. In vitro PCS or IS blocked CD4+ T cell proliferation, induced apoptosis, and diminished the expression of mitochondrial proteins. Electron microscopy imaging revealed perturbations of mitochondrial networks similar to those found in INRs following incubation of healthy memory CD4+ T cells with PCS. Using bacterial 16S rDNA, INR stool samples were found enriched in proteolytic bacterial genera that metabolize tyrosine and phenylalanine to produce PCS. We propose that toxic solutes from the gut bacterial flora may impair CD4+ T cell recovery during ART and may contribute to CD4+ T cell lymphopenia characteristic of INRs.
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Affiliation(s)
- Brian Ferrari
- Department of Medicine, Division of Infectious Diseases and HIV Medicine, Center for AIDS Research, Case Western Reserve University/University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA
| | - Amanda Cabral Da Silva
- Department of Pathology, Pathology Advanced Translational Research (PATRU), School of Medicine and
| | - Ken H. Liu
- Clinical Biomarkers Laboratory, Department of Medicine, Emory University, Atlanta, Georgia, USA
| | - Evgeniya V. Saidakova
- Institute of Ecology and Genetics of Microorganisms, Perm Federal Research Center Ural Branch Russian Academy of Sciences, Perm, Russia
- Department of Microbiology and Immunology, Perm State University, Perm, Russia
| | - Larisa B. Korolevskaya
- Institute of Ecology and Genetics of Microorganisms, Perm Federal Research Center Ural Branch Russian Academy of Sciences, Perm, Russia
| | - Konstantin V. Shmagel
- Institute of Ecology and Genetics of Microorganisms, Perm Federal Research Center Ural Branch Russian Academy of Sciences, Perm, Russia
| | - Carey Shive
- Department of Medicine, Division of Infectious Diseases and HIV Medicine, Center for AIDS Research, Case Western Reserve University/University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA
- Cleveland VA Medical Center, Cleveland, Ohio, USA
| | - Gabriela Pacheco Sanchez
- Department of Pathology, Pathology Advanced Translational Research (PATRU), School of Medicine and
| | - Mauricio Retuerto
- Institute of Ecology and Genetics of Microorganisms, Perm Federal Research Center Ural Branch Russian Academy of Sciences, Perm, Russia
| | | | - Khader Ghneim
- Department of Microbiology and Immunology, Perm State University, Perm, Russia
| | - Laura Noel-Romas
- Integrated Microbiome Core, Department of Dermatology, Case Western Reserve University/University Hospitals Case Medical Center, Cleveland, Ohio, USA
- Center for Global Health and Diseases, Case Western Reserve University, Cleveland, Ohio, USA
| | - Benigno Rodriguez
- Department of Medicine, Division of Infectious Diseases and HIV Medicine, Center for AIDS Research, Case Western Reserve University/University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA
| | - Mahmoud A. Ghannoum
- Integrated Microbiome Core, Department of Dermatology, Case Western Reserve University/University Hospitals Case Medical Center, Cleveland, Ohio, USA
| | - Peter P. Hunt
- Department of Medicine, UCSF, San Francisco, California, USA
| | - Steven G. Deeks
- Department of Medicine, UCSF, San Francisco, California, USA
| | - Adam D. Burgener
- Center for Global Health and Diseases, Case Western Reserve University, Cleveland, Ohio, USA
- Department of Obstetrics & Gynecology, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Dean P. Jones
- Clinical Biomarkers Laboratory, Department of Medicine, Emory University, Atlanta, Georgia, USA
| | - Mirela A. Dobre
- Department of Medicine (Nephrology), Case Western Reserve University/University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA
| | - Vincent C. Marconi
- Division of Infectious Diseases, Department of Global Health, and Department of Global Health, Rollins School of Public Health, Atlanta, Georgia, USA
| | - Rafick-Pierre Sekaly
- Department of Pathology, Pathology Advanced Translational Research (PATRU), School of Medicine and
| | - Souheil-Antoine Younes
- Department of Pathology, Pathology Advanced Translational Research (PATRU), School of Medicine and
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Global transcriptomic characterization of T cells in individuals with chronic HIV-1 infection. Cell Discov 2022; 8:29. [PMID: 35351857 PMCID: PMC8964811 DOI: 10.1038/s41421-021-00367-x] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Accepted: 12/08/2021] [Indexed: 12/14/2022] Open
Abstract
To obtain a comprehensive scenario of T cell profiles and synergistic immune responses, we performed single-cell RNA sequencing (scRNA-seq) on the peripheral T cells of 14 individuals with chronic human immunodeficiency virus 1 (HIV-1) infection, including nine treatment-naive (TP) and eight antiretroviral therapy (ART) participants (of whom three were paired with TP cases), and compared the results with four healthy donors (HD). Through analyzing the transcriptional profiles of CD4+ and CD8+ T cells, coupled with assembled T cell receptor sequences, we observed the significant loss of naive T cells, prolonged inflammation, and increased response to interferon-α in TP individuals, which could be partially restored by ART. Interestingly, we revealed that CD4+ and CD8+ Effector-GNLY clusters were expanded in TP cases, and persistently increased in ART individuals where they were typically correlated with poor immune restoration. This transcriptional dataset enables a deeper understanding of the pathogenesis of HIV-1 infection and is also a rich resource for developing novel immune targeted therapeutic strategies.
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Younes SA. Mitochondrial Exhaustion of Memory CD4 T-Cells in Treated HIV-1 Infection. IMMUNOMETABOLISM 2022; 4:e220013. [PMID: 35633761 PMCID: PMC9140223 DOI: 10.20900/immunometab20220013] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/29/2023]
Abstract
People living with HIV (PLWH) who are immune non-responders (INR) to therapy are unable to restore their CD4 T-cell count and remain at great risk of morbidity and mortality. Here the mitochondrial defects that characterize memory CD4 T-cells in INR and causes of this mitochondrial exhaustion are reviewed. This review also describes the various reagents used to induce the expression of the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), the master regulator of mitochondrial biogenesis, which can restore mitochondria fitness and CD4 T-cell proliferation in INR. Due to sustained heightened inflammation in INR, the mitochondrial network is unable to be rejuvenated and requires attenuation of mediators of inflammation to rescue mitochondria and CD4 T-cell counts in INR.
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Affiliation(s)
- Souheil-Antoine Younes
- Department of Pathology, Pathology Advanced Translational Research (PATRU), School of Medicine, Emory University, Atlanta 30322, USA
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Yan J, Ouyang J, Isnard S, Zhou X, Harypursat V, Routy JP, Chen Y. Alcohol Use and Abuse Conspires With HIV Infection to Aggravate Intestinal Dysbiosis and Increase Microbial Translocation in People Living With HIV: A Review. Front Immunol 2021; 12:741658. [PMID: 34975838 PMCID: PMC8718428 DOI: 10.3389/fimmu.2021.741658] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 11/30/2021] [Indexed: 12/12/2022] Open
Abstract
The intestinal microbiome is an essential so-called human "organ", vital for the induction of innate immunity, for metabolizing nutrients, and for maintenance of the structural integrity of the intestinal barrier. HIV infection adversely influences the richness and diversity of the intestinal microbiome, resulting in structural and functional impairment of the intestinal barrier and an increased intestinal permeability. Pathogens and metabolites may thus cross the "leaky" intestinal barrier and enter the systemic circulation, which is a significant factor accounting for the persistent underlying chronic inflammatory state present in people living with HIV (PLWH). Additionally, alcohol use and abuse has been found to be prevalent in PLWH and has been strongly associated with the incidence and progression of HIV/AIDS. Recently, converging evidence has indicated that the mechanism underlying this phenomenon is related to intestinal microbiome and barrier function through numerous pathways. Alcohol acts as a "partner" with HIV in disrupting microbiome ecology, and thus impairing of the intestinal barrier. Optimizing the microbiome and restoring the integrity of the intestinal barrier is likely to be an effective adjunctive therapeutic strategy for PLWH. We herein critically review the interplay among HIV, alcohol, and the gut barrier, thus setting the scene with regards to development of effective strategies to counteract the dysregulated gut microbiome and the reduction of microbial translocation and inflammation in PLWH.
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Affiliation(s)
- Jiangyu Yan
- Clinical Research Center, Chongqing Public Health Medical Center, Chongqing, China
| | - Jing Ouyang
- Clinical Research Center, Chongqing Public Health Medical Center, Chongqing, China
| | - Stéphane Isnard
- Infectious Diseases and Immunity in Global Health Program, Research Institute, McGill University Health Centre, Montréal, QC, Canada
- Chronic Viral Illness Service, McGill University Health Centre, Montréal, QC, Canada
- Canadian HIV Trials Network (CTN), Canadian Institutes of Health Research (CIHR), Vancouver, BC, Canada
| | - Xin Zhou
- Clinical Research Center, Chongqing Public Health Medical Center, Chongqing, China
| | - Vijay Harypursat
- Clinical Research Center, Chongqing Public Health Medical Center, Chongqing, China
| | - Jean-Pierre Routy
- Infectious Diseases and Immunity in Global Health Program, Research Institute, McGill University Health Centre, Montréal, QC, Canada
- Chronic Viral Illness Service, McGill University Health Centre, Montréal, QC, Canada
- Division of Hematology, McGill University Health Centre, Montréal, QC, Canada
| | - Yaokai Chen
- Clinical Research Center, Chongqing Public Health Medical Center, Chongqing, China
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Márquez-Coello M, Ruiz-Sánchez C, Martín-Aspas A, Fernández Gutiérrez Del Álamo C, Illanes-Álvarez F, Cuesta-Sancho S, Girón-González JA. Neutrophil Expression of T and B Immunomodulatory Molecules in HIV Infection. Front Immunol 2021; 12:670966. [PMID: 34975826 PMCID: PMC8718872 DOI: 10.3389/fimmu.2021.670966] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 11/29/2021] [Indexed: 01/15/2023] Open
Abstract
ObjectiveEvaluate the expression of B and T cell immunomodulatory molecules in polymorphonuclear neutrophils (PMN) in HIV-infected patients.MethodsHIV load, bacterial translocation and neutrophils’ expression of T [programmed death ligand, interleukin-10+, arginase 1+] and B [BAFF, APRIL] molecules were analyzed in different cohorts and time points: a control group of 25 healthy individuals and two groups of HIV-infected patients. Group 1 of patients included 35 untreated patients, studied at baseline and after antiretroviral therapy (ART). Group 2 was composed of 25 patients with undetectable viral load after a median of 101 months of ART prior to inclusion in the study.ResultsCompared with the control group, group 1 patients showed increased bacterial translocation and their PMN had a significantly higher expression of T and B-cell immunomodulatory molecules, both at baseline and after 12 months of ART. Group 2 patients showed reduced bacterial translocation levels when compared with group 1 patients after 12 months of treatment. PMN expression of B-cell modulators was similar between group 2 patients and healthy controls, although the expression of T-cell modulators remained increased.ConclusionIn HIV-infected patients, the expression of B-cell stimulatory and T-cell suppressive molecules by neutrophils was increased at baseline and after a limited time of therapy. After a prolonged period of ART, only PMNs expression of T-cell immunosuppressive molecules remained elevated.
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Affiliation(s)
- Mercedes Márquez-Coello
- Unidad de Enfermedades Infecciosas, Servicio de Medicina Interna, Hospital Universitario Puerta del Mar, Facultad de Medicina, Universidad de Cádiz, Cádiz, Spain
- Instituto de Investigación e Innovación en Ciencias Biomédicas de Cádiz (INiBICA), Cádiz, Spain
| | - Cristina Ruiz-Sánchez
- Unidad de Enfermedades Infecciosas, Servicio de Medicina Interna, Hospital Universitario Puerta del Mar, Facultad de Medicina, Universidad de Cádiz, Cádiz, Spain
- Instituto de Investigación e Innovación en Ciencias Biomédicas de Cádiz (INiBICA), Cádiz, Spain
| | - Andrés Martín-Aspas
- Unidad de Enfermedades Infecciosas, Servicio de Medicina Interna, Hospital Universitario Puerta del Mar, Facultad de Medicina, Universidad de Cádiz, Cádiz, Spain
- Instituto de Investigación e Innovación en Ciencias Biomédicas de Cádiz (INiBICA), Cádiz, Spain
| | - Clotilde Fernández Gutiérrez Del Álamo
- Instituto de Investigación e Innovación en Ciencias Biomédicas de Cádiz (INiBICA), Cádiz, Spain
- Servicio de Microbiología, Hospital Universitario Puerta del Mar, Facultad de Medicina, Universidad de Cádiz, Cádiz, Spain
| | - Francisco Illanes-Álvarez
- Unidad de Enfermedades Infecciosas, Servicio de Medicina Interna, Hospital Universitario Puerta del Mar, Facultad de Medicina, Universidad de Cádiz, Cádiz, Spain
- Instituto de Investigación e Innovación en Ciencias Biomédicas de Cádiz (INiBICA), Cádiz, Spain
| | - Sara Cuesta-Sancho
- Unidad de Enfermedades Infecciosas, Servicio de Medicina Interna, Hospital Universitario Puerta del Mar, Facultad de Medicina, Universidad de Cádiz, Cádiz, Spain
- Instituto de Investigación e Innovación en Ciencias Biomédicas de Cádiz (INiBICA), Cádiz, Spain
| | - José-Antonio Girón-González
- Unidad de Enfermedades Infecciosas, Servicio de Medicina Interna, Hospital Universitario Puerta del Mar, Facultad de Medicina, Universidad de Cádiz, Cádiz, Spain
- Instituto de Investigación e Innovación en Ciencias Biomédicas de Cádiz (INiBICA), Cádiz, Spain
- *Correspondence: José-Antonio Girón-González,
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Crespo-Bermejo C, de Arellano ER, Lara-Aguilar V, Valle-Millares D, Gómez-Lus ML, Madrid R, Martín-Carbonero L, Briz V. Persistent low-Level viremia in persons living with HIV undertreatment: An unresolved status. Virulence 2021; 12:2919-2931. [PMID: 34874239 PMCID: PMC8654475 DOI: 10.1080/21505594.2021.2004743] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Antiretroviral therapy (ART) allows suppressed viremia to reach less than 50 copies/mL in most treated persons living with HIV (PLWH). However, the existence of PLWH that show events of persistent low-level viremia (pLLV) between 50 and 1000 copies/mL and with different virological consequences have been observed. PLLV has been associated with higher virological failure (VF), viral genotype resistance, adherence difficulties and AIDS events. Moreover, some reports show that pLLV status can lead to residual immune activation and inflammation, with an increased risk of immunovirological failure and a pro-inflammatory cytokine level which can lead to a higher occurrence of non-AIDS defining events (NADEs) and other adverse clinical outcomes. Until now, however, published data have shown controversial results that hinder understanding of the true cause(s) and origin(s) of this phenomenon. Molecular mechanisms related to viral reservoir size and clonal expansion have been suggested as the possible origin of pLLV. This review aims to assess recent findings to provide a global view of the role of pLLV in PLWH and the impact this status may cause on the clinical progression of these patients.
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Affiliation(s)
- Celia Crespo-Bermejo
- Laboratory of Reference and Research on Viral Hepatitis, National Center of Microbiology, Institute of Health Carlos Iii, Majadahonda, Madrid, Spain
| | - Eva Ramírez de Arellano
- Laboratory of Reference and Research on Viral Hepatitis, National Center of Microbiology, Institute of Health Carlos Iii, Majadahonda, Madrid, Spain
| | - Violeta Lara-Aguilar
- Laboratory of Reference and Research on Viral Hepatitis, National Center of Microbiology, Institute of Health Carlos Iii, Majadahonda, Madrid, Spain
| | - Daniel Valle-Millares
- Laboratory of Reference and Research on Viral Hepatitis, National Center of Microbiology, Institute of Health Carlos Iii, Majadahonda, Madrid, Spain
| | - Mª Luisa Gómez-Lus
- Departamento de Medicina- Área de Microbiología. Facultad de Medicina. Universidad Complutense, Madrid, Spain
| | - Ricardo Madrid
- Parque Científico de Madrid, Campus de Cantoblanco, Madrid, Spain.,Department of Genetics, Physiology and Microbiology. Faculty of Biology, Complutense University of Madrid, Madrid, Spain
| | - Luz Martín-Carbonero
- Unidad de Vih. Servicio de Medicina Interna. Hospital Universitario La Paz. Instituto de Investigación Sanitaria Hospital de La Paz (Idipaz), Madrid, Spain
| | - Verónica Briz
- Laboratory of Reference and Research on Viral Hepatitis, National Center of Microbiology, Institute of Health Carlos Iii, Majadahonda, Madrid, Spain
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Abstract
Purpose of Review Observations of differing bacterial, intestinal microbiomes in people living with HIV have propelled interest in contributions of the microbiome to HIV disease. Non-human primate (NHP) models of HIV infection provide a controlled setting for assessing contributions of the microbiome by standardizing environmental confounders. We provide an overview of the findings of microbiome contributions to aspects of HIV disease derived from these animal models. Recent Findings Observations of differing bacterial, intestinal microbiomes are inconsistently observed in the NHP model following SIV infection. Differences in lentiviral susceptibility and vaccine efficacy have been attributed to variations in the intestinal microbiome; however, by-and-large, these differences have not been experimentally assessed. Summary Although compelling associations exist, clearly defined contributions of the microbiome to HIV and SIV disease are lacking. The empirical use of comprehensive multi-omics assessments and longitudinal and interventional study designs in NHP models is necessary to define this contribution more clearly.
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Affiliation(s)
- Jason M Brenchley
- Barrier Immunity Section, Laboratory of Viral Diseases, National Institutes of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, USA
| | - Alexandra M Ortiz
- Barrier Immunity Section, Laboratory of Viral Diseases, National Institutes of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, USA.
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Bavaro DF, Laghetti P, Poliseno M, De Gennaro N, Di Gennaro F, Saracino A. A Step Closer to the "Fourth 90": A Practical Narrative Review of Diagnosis and Management of Nutritional Issues of People Living with HIV. Diagnostics (Basel) 2021; 11:2047. [PMID: 34829394 PMCID: PMC8618448 DOI: 10.3390/diagnostics11112047] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 11/01/2021] [Accepted: 11/02/2021] [Indexed: 12/02/2022] Open
Abstract
The quality of life of people living with HIV (PLWH) has remarkably increased thanks to the introduction of combined antiretroviral therapy. Still, PLWH are exposed to an increased risk of cardiovascular diseases, diabetes, chronic kidney disease, and liver disease. Hence, the purpose of this review is to summarize the current knowledge about diagnosis and nutritional management with specific indication of macro and micronutrients intake for the main comorbidities of PLWH. In fact, a prompt diagnosis and management of lifestyle behaviors are fundamental steps to reach the "fourth 90". To achieve an early diagnosis of these comorbidities, clinicians have at their disposal algorithms such as the Framingham Score to assess cardiovascular risk; transient elastography and liver biopsy to detect NAFLD and NASH; and markers such as the oral glucose tolerance test and GFR to identify glucose impairment and renal failure, respectively. Furthermore, maintenance of ideal body weight is the goal for reducing cardiovascular risk and to improve diabetes, steatosis and fibrosis; while Mediterranean and low-carbohydrate diets are the dietetic approaches proposed for cardioprotective effects and for glycemic control, respectively. Conversely, diet management of chronic kidney disease requires different nutritional assessment, especially regarding protein intake, according to disease stage and eventually concomitant diabetes.
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Affiliation(s)
- Davide Fiore Bavaro
- Clinic of Infectious Diseases, University Hospital Policlinico, University of Bari, 70124 Bari, Italy; (P.L.); (N.D.G.); (F.D.G.); (A.S.)
| | - Paola Laghetti
- Clinic of Infectious Diseases, University Hospital Policlinico, University of Bari, 70124 Bari, Italy; (P.L.); (N.D.G.); (F.D.G.); (A.S.)
| | | | - Nicolò De Gennaro
- Clinic of Infectious Diseases, University Hospital Policlinico, University of Bari, 70124 Bari, Italy; (P.L.); (N.D.G.); (F.D.G.); (A.S.)
| | - Francesco Di Gennaro
- Clinic of Infectious Diseases, University Hospital Policlinico, University of Bari, 70124 Bari, Italy; (P.L.); (N.D.G.); (F.D.G.); (A.S.)
| | - Annalisa Saracino
- Clinic of Infectious Diseases, University Hospital Policlinico, University of Bari, 70124 Bari, Italy; (P.L.); (N.D.G.); (F.D.G.); (A.S.)
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Ali Z, Shahzadi I, Majeed A, Malik HMT, Waseem S, Ahmed I, Anis RA, Saeed S, Anees M. Comparative analysis of the serum microbiome of HIV infected individuals. Genomics 2021; 113:4015-4021. [PMID: 34637930 DOI: 10.1016/j.ygeno.2021.10.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 10/02/2021] [Accepted: 10/07/2021] [Indexed: 11/15/2022]
Abstract
HIV infects the CD4 cells which marks the suppression of our immune system. DNA from serum of healthy, treated and untreated HIV infected individuals was extracted. The DNA was subjected to 16S metagenomic sequencing and analyzed using QIIME2 pipeline. 16S sequencing analysis showed serum microbiome was dominated by Firmicutes, Proteobacteria, Bacteroidota and Actinobacteria. Treated HIV infection showed highest abundance of Firmicutes (66.40%) significantly higher than untreated HIV infection (35.88%) and control (41.89%). Bacilli was most abundant class in treated (63.59%) and second most abundant in untreated (34.53%) while control group showed highest abundance of class Gamma-proteobacteria (45.86%). Untreated HIV infection group showed Enterococcus (10.72%) and Streptococcus (6.599%) as the most abundant species. Untreated HIV infection showed significantly higher (p = 0.0039) species richness than treated and control groups. An altered serum microbiome of treated HIV infection and higher microbial abundance in serum of untreated HIV infection was observed.
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Affiliation(s)
- Zain Ali
- Department of Biochemistry, Quaid-i-Azam University, Islamabad, Pakistan
| | - Iram Shahzadi
- Department of Biochemistry, Quaid-i-Azam University, Islamabad, Pakistan
| | - Aqsa Majeed
- Alpha Genomics (Pvt) Ltd., Islamabad, Pakistan
| | | | | | - Ibrar Ahmed
- Alpha Genomics (Pvt) Ltd., Islamabad, Pakistan
| | - Riffat Aysha Anis
- Institute of Diet and Nutritional Sciences, University of Lahore, Islamabad Campus, Pakistan
| | - Sadia Saeed
- Institute of Biochemistry and Biotechnology, University of Arid Agriculture, Rawalpindi, Pakistan
| | - Mariam Anees
- Department of Biochemistry, Quaid-i-Azam University, Islamabad, Pakistan.
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Ishizaka A, Koga M, Mizutani T, Parbie PK, Prawisuda D, Yusa N, Sedohara A, Kikuchi T, Ikeuchi K, Adachi E, Koibuchi T, Furukawa Y, Tojo A, Imoto S, Suzuki Y, Tsutsumi T, Kiyono H, Matano T, Yotsuyanagi H. Unique Gut Microbiome in HIV Patients on Antiretroviral Therapy (ART) Suggests Association with Chronic Inflammation. Microbiol Spectr 2021; 9:e0070821. [PMID: 34378948 PMCID: PMC8552706 DOI: 10.1128/spectrum.00708-21] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Accepted: 07/13/2021] [Indexed: 02/07/2023] Open
Abstract
Chronic inflammation is a hallmark of human immunodeficiency virus (HIV) infection and a risk factor for the development and progression of age-related comorbidities. Although HIV-associated gut dysbiosis has been suggested to be involved in sustained chronic inflammation, there remains a limited understanding of the association between gut dysbiosis and chronic inflammation during HIV infection. Here, we investigated compositional changes in the gut microbiome and its role in chronic inflammation in patients infected with HIV. We observed that the gut microbiomes of patients with low CD4 counts had reduced alpha diversity compared to those in uninfected controls. Following CD4 recovery, alpha diversity was restored, but intergroup dissimilarity of bacterial composition remained unchanged between patients and uninfected controls. Patients with HIV had higher abundance of the classes Negativicutes, Bacilli, and Coriobacteriia, as well as depletion of the class Clostridia. These relative abundances positively correlated with inflammatory cytokines and negatively correlated with anti-inflammatory cytokines. We found that gut dysbiosis accompanying HIV infection was characterized by a depletion of obligate anaerobic Clostridia and enrichment of facultative anaerobic bacteria, reflecting increased intestinal oxygen levels and intestinal permeability. Furthermore, it is likely that HIV-associated dysbiosis shifts the immunological balance toward inflammatory Th1 responses and encourages proinflammatory cytokine production. Our results suggest that gut dysbiosis contributes to sustaining chronic inflammation in patients with HIV infection despite effective antiretroviral therapy and that correcting gut dysbiosis will be effective in improving long-term outcomes in patients. IMPORTANCE Chronic inflammation is a hallmark of HIV infection and is associated with the development and progression of age-related comorbidities. Although the gastrointestinal tract is a major site of HIV replication and CD4+ T-cell depletion, the role of HIV-associated imbalance of gut microbiome in chronic inflammation is unclear. Here, we aimed to understand the causal relationship between abnormalities in the gut microbiome and chronic inflammation in patients with HIV. Our results suggest HIV-associated gut dysbiosis presents a more aerobic environment than that of healthy individuals, despite prolonged viral suppression. This dysbiosis likely results from a sustained increase in intestinal permeability, which supports sustained bacterial translocation in HIV patients, despite effective therapy. Additionally, we observed that several bacterial taxa enriched in HIV patients were associated with increased expression of inflammatory cytokines. Collectively, these results suggest that gut dysbiosis plays an important role in chronic inflammation in HIV patients.
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Affiliation(s)
- Aya Ishizaka
- Division of Infectious Diseases, Advanced Clinical Research Center, the Institute of Medical Science, The University of Tokyo, Tokyo, Japan
- International Research and Development Center for Mucosal Vaccines, the Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Michiko Koga
- Division of Infectious Diseases, Advanced Clinical Research Center, the Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Taketoshi Mizutani
- Division of Infectious Diseases, Advanced Clinical Research Center, the Institute of Medical Science, The University of Tokyo, Tokyo, Japan
- International Research and Development Center for Mucosal Vaccines, the Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Prince Kofi Parbie
- AIDS Research Center, National Institute of Infectious Diseases, Tokyo, Japan
| | - Diki Prawisuda
- Division of Infectious Diseases, Advanced Clinical Research Center, the Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Nozomi Yusa
- Department of Applied Genomics, Research Hospital, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Ayako Sedohara
- Division of Infectious Diseases, Advanced Clinical Research Center, the Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Tadashi Kikuchi
- AIDS Research Center, National Institute of Infectious Diseases, Tokyo, Japan
- Department of Infectious Diseases and Applied Immunology, IMSUT Hospital of Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Kazuhiko Ikeuchi
- Department of Infectious Diseases and Applied Immunology, IMSUT Hospital of Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Eisuke Adachi
- Department of Infectious Diseases and Applied Immunology, IMSUT Hospital of Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Tomohiko Koibuchi
- Department of Infectious Diseases and Applied Immunology, IMSUT Hospital of Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Yoichi Furukawa
- Department of Applied Genomics, Research Hospital, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Arinobu Tojo
- Department of Laboratory Medicine, Research Hospital, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Seiya Imoto
- Division of Health Medical Data Science, Health Intelligence Center, the Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Yutaka Suzuki
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan
| | - Takeya Tsutsumi
- Division of Infectious Diseases, Advanced Clinical Research Center, the Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Hiroshi Kiyono
- International Research and Development Center for Mucosal Vaccines, the Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Tetsuro Matano
- AIDS Research Center, National Institute of Infectious Diseases, Tokyo, Japan
- Department of AIDS Vaccine Development, IMSUT Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Hiroshi Yotsuyanagi
- Division of Infectious Diseases, Advanced Clinical Research Center, the Institute of Medical Science, The University of Tokyo, Tokyo, Japan
- Department of Infectious Diseases and Applied Immunology, IMSUT Hospital of Institute of Medical Science, The University of Tokyo, Tokyo, Japan
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Corley MJ, Sacdalan C, Pang APS, Chomchey N, Ratnaratorn N, Valcour V, Kroon E, Cho KS, Belden AC, Colby D, Robb M, Hsu D, Spudich S, Paul R, Vasan S, Ndhlovu LC. Abrupt and altered cell-type specific DNA methylation profiles in blood during acute HIV infection persists despite prompt initiation of ART. PLoS Pathog 2021; 17:e1009785. [PMID: 34388205 PMCID: PMC8386872 DOI: 10.1371/journal.ppat.1009785] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 08/25/2021] [Accepted: 07/06/2021] [Indexed: 02/06/2023] Open
Abstract
HIV-1 disrupts the host epigenetic landscape with consequences for disease pathogenesis, viral persistence, and HIV-associated comorbidities. Here, we examined how soon after infection HIV-associated epigenetic changes may occur in blood and whether early initiation of antiretroviral therapy (ART) impacts epigenetic modifications. We profiled longitudinal genome-wide DNA methylation in monocytes and CD4+ T lymphocytes from 22 participants in the RV254/SEARCH010 acute HIV infection (AHI) cohort that diagnoses infection within weeks after estimated exposure and immediately initiates ART. We identified monocytes harbored 22,697 differentially methylated CpGs associated with AHI compared to 294 in CD4+ T lymphocytes. ART minimally restored less than 1% of these changes in monocytes and had no effect upon T cells. Monocyte DNA methylation patterns associated with viral load, CD4 count, CD4/CD8 ratio, and longitudinal clinical phenotypes. Our findings suggest HIV-1 rapidly embeds an epigenetic memory not mitigated by ART and support determining epigenetic signatures in precision HIV medicine. Trial Registration:NCT00782808 and NCT00796146. The epigenetic marker, DNA methylation, plays a key role regulating the immune system during host-pathogen interactions. Using cell-type specific DNA methylation profiling, we explored whether epigenetic changes occurred soon after HIV infection and following early treatment with anti-HIV drugs. Acute infection was associated with early DNA methylation changes in purified monocytes and CD4+ T cells isolated from blood. In monocytes, rapid anti-HIV treatment minimally restored DNA methylation changes associated with infection and unexpectedly had no impact in CD4+ T cells. DNA methylation patterns before treatment informed long term clinical outcomes including CD4+ T cell counts and favorable clinical phenotypes. These findings identify candidates for consideration in epigenome editing approaches in HIV prevention, treatment, and cure strategies.
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Affiliation(s)
- Michael J. Corley
- Department of Medicine, Division of Infectious Diseases, Weill Cornell Medicine; New York, New York, United States of America
| | - Carlo Sacdalan
- Institute of HIV Research and Innovation; Bangkok, Thailand
- SEARCH, South East Asia Research Collaboration in HIV; Bangkok, Thailand
| | - Alina P. S. Pang
- Department of Medicine, Division of Infectious Diseases, Weill Cornell Medicine; New York, New York, United States of America
| | - Nitiya Chomchey
- Institute of HIV Research and Innovation; Bangkok, Thailand
- SEARCH, South East Asia Research Collaboration in HIV; Bangkok, Thailand
| | | | - Victor Valcour
- Memory and Aging Center, University of California San Francisco; San Francisco, California, United States of America
| | - Eugene Kroon
- Institute of HIV Research and Innovation; Bangkok, Thailand
- SEARCH, South East Asia Research Collaboration in HIV; Bangkok, Thailand
| | - Kyu S. Cho
- Missouri Institute of Mental Health University of Missouri; St. Louis, Missouri, United States of America
| | - Andrew C. Belden
- Missouri Institute of Mental Health University of Missouri; St. Louis, Missouri, United States of America
| | - Donn Colby
- Institute of HIV Research and Innovation; Bangkok, Thailand
- SEARCH, South East Asia Research Collaboration in HIV; Bangkok, Thailand
| | - Merlin Robb
- Armed Forces Research Institute of Medical Sciences; Bangkok, Thailand
- Henry M. Jackson Foundation for the Advancement of Military Medicine; Bethesda, Maryland, United States of America
| | - Denise Hsu
- Armed Forces Research Institute of Medical Sciences; Bangkok, Thailand
- Henry M. Jackson Foundation for the Advancement of Military Medicine; Bethesda, Maryland, United States of America
| | - Serena Spudich
- Department of Neurology, Yale University; New Haven, Connecticut, United States of America
| | - Robert Paul
- Missouri Institute of Mental Health University of Missouri; St. Louis, Missouri, United States of America
| | - Sandhya Vasan
- Henry M. Jackson Foundation for the Advancement of Military Medicine; Bethesda, Maryland, United States of America
- US Military HIV Research Program; Silver Spring, Maryland, United States of America
| | - Lishomwa C. Ndhlovu
- Department of Medicine, Division of Infectious Diseases, Weill Cornell Medicine; New York, New York, United States of America
- * E-mail:
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Hileman CO, Kalayjian RC, Azzam S, Schlatzer D, Wu K, Tassiopoulos K, Bedimo R, Ellis RJ, Erlandson KM, Kallianpur A, Koletar SL, Landay AL, Palella FJ, Taiwo B, Pallaki M, Hoppel CL. Plasma Citrate and Succinate Are Associated With Neurocognitive Impairment in Older People With HIV. Clin Infect Dis 2021; 73:e765-e772. [PMID: 33564870 DOI: 10.1093/cid/ciab107] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Neurocognitive impairment (NCI) is associated with monocyte activation in people with HIV (PWH). Activated monocytes increase glycolysis, reduce oxidative phosphorylation, and accumulate citrate and succinate, tricarboxylic acid (TCA) cycle metabolites that promote inflammation-this metabolic shift may contribute to NCI and slowed gait speed in PWH. METHODS Plasma citrate and succinate were assayed by liquid chromatography-mass spectrometry from 957 participants upon entry to a multicenter, prospective cohort of older PWH. Logistic, linear, and mixed-effects linear regression models were used to examine associations between entry/baseline TCA cycle metabolites and cross-sectional and longitudinal NCI, neuropsychological test scores (NPZ-4), and gait speed. RESULTS Median age was 51 (range 40-78) years. Each 1 standard deviation (SD) citrate increment was associated with 1.18 higher odds of prevalent NCI at baseline (P = .03), 0.07 SD lower time-updated NPZ-4 score (P = .01), and 0.02 m/s slower time-updated gait speed (P < .0001). Age accentuated these effects. In the oldest age-quartile, higher citrate was associated with 1.64 higher odds of prevalent NCI, 0.17 SD lower NPZ-4, and 0.04 m/s slower gait speed (P ≤ .01 for each). Similar associations were apparent with succinate in the oldest age-quintile, but not with gait speed. In participants without NCI at entry, higher citrate predicted a faster rate of neurocognitive decline. CONCLUSIONS Higher plasma citrate and succinate are associated with worse cross-sectional and longitudinal measures of neurocognitive function and gait speed that are age-dependent, supporting the importance of altered bioenergetic metabolism in the pathogenesis of NCI in older PWH.
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Affiliation(s)
- Corrilynn O Hileman
- Department of Medicine, Division of Infectious Diseases, MetroHealth Medical Center and Case Western Reserve School of Medicine, Cleveland, Ohio, USA
| | - Robert C Kalayjian
- Department of Medicine, Division of Infectious Diseases, MetroHealth Medical Center and Case Western Reserve School of Medicine, Cleveland, Ohio, USA
| | - Sausan Azzam
- Department of Nutrition, Proteomics and Small Molecule Mass Spectrometry, Case Western Reserve School of Medicine, Cleveland, Ohio, USA
| | - Daniela Schlatzer
- Department of Nutrition, Proteomics and Small Molecule Mass Spectrometry, Case Western Reserve School of Medicine, Cleveland, Ohio, USA
| | - Kunling Wu
- Center for Biostatistics in AIDS Research, Harvard T. H. Chan School of Public Health, Boston, Massachussets, USA
| | - Katherine Tassiopoulos
- Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachussets, USA
| | - Roger Bedimo
- Infectious Diseases Section, VA North Texas Health Care System, Dallas, Texas, USA
| | - Ronald J Ellis
- Department of Neurosciences, Psychiatry and Medicine, University of California, San Diego, California, USA
| | - Kristine M Erlandson
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Columbus, USA
| | - Asha Kallianpur
- Genomic Medicine Institute, Cleveland Clinic Lerner Research Institute, Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA
| | - Susan L Koletar
- Department of Medicine, The Ohio State University Medical Center, Columbus, Ohio, USA
| | - Alan L Landay
- Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA
| | - Frank J Palella
- Department of Medicine, Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Babafemi Taiwo
- Department of Medicine, Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Muralidhar Pallaki
- Department of Medicine Louis Stokes Cleveland VA Medical Center and Case Western Reserve School of Medicine, Cleveland, Ohio, USA
| | - Charles L Hoppel
- Center for Mitochondrial Disease and Department of Pharmacology, Case Western Reserve University and Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
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Basile FW, Fedele MC, Lo Vecchio A. Gastrointestinal Diseases in Children Living with HIV. Microorganisms 2021; 9:microorganisms9081572. [PMID: 34442651 PMCID: PMC8398799 DOI: 10.3390/microorganisms9081572] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2021] [Revised: 07/19/2021] [Accepted: 07/21/2021] [Indexed: 12/12/2022] Open
Abstract
Thanks to the advances in antiretroviral therapies (ART) and early diagnosis, pediatric HIV has turned into a chronic infection that requires the collaboration of all pediatric subspecialists for holistic patient management. Gastrointestinal complaints are a frequent reason for seeking access to medical care in all pediatric patients worldwide. Intestinal involvement is present in virtually all children with HIV infections. In high-prevalence settings, up to 25% of children accessing the hospital for diarrhea are diagnosed with HIV. More than half of patients with advanced disease present with gastrointestinal symptoms, from mild infectious diarrhea to severe gastrointestinal impairment, malabsorption and failure to thrive. Gastrointestinal disorders do not spare children on ART, particularly in the initial months of therapy. ART-associated pancreatitis and hepatitis are rare but potentially severe adverse events, whereas lower abdominal symptoms have been reported in more than a third of patients. The latter are usually mild and transient, but may limit ART adherence; a correct framing of the problem is necessary to minimize therapy switches while optimizing the quality of life of children on ART. This review aims to provide state-of-the-art guidance for the initial approach to gastrointestinal diseases in children living with HIV.
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Affiliation(s)
- Francesca Wanda Basile
- Baylor International Pediatric AIDS Initiative, Pediatrics, Baylor College of Medicine, 1100 Bates Street, Houston, TX 77030, USA;
| | - Maria Cristina Fedele
- Department of Woman, Child and of General and Specialized Surgery, University of Campania “Luigi Vanvitelli”, Via Luigi De Crecchio 2, 80138 Naples, Italy;
| | - Andrea Lo Vecchio
- Department of Translational Medical Science, Section of Pediatrics—University of Naples Federico II, 80131 Naples, Italy
- Correspondence: ; Tel.: +39-081-7463365; Fax: +39-081-7464232
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Zozaya-Valdés E, Wong SQ, Raleigh J, Hatzimihalis A, Ftouni S, Papenfuss AT, Sandhu S, Dawson MA, Dawson SJ. Detection of cell-free microbial DNA using a contaminant-controlled analysis framework. Genome Biol 2021; 22:187. [PMID: 34162397 PMCID: PMC8220693 DOI: 10.1186/s13059-021-02401-3] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Accepted: 06/04/2021] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND The human microbiome plays an important role in cancer. Accumulating evidence indicates that commensal microbiome-derived DNA may be represented in minute quantities in the cell-free DNA of human blood and could possibly be harnessed as a new cancer biomarker. However, there has been limited use of rigorous experimental controls to account for contamination, which invariably affects low-biomass microbiome studies. RESULTS We apply a combination of 16S-rRNA-gene sequencing and droplet digital PCR to determine if the specific detection of cell-free microbial DNA (cfmDNA) is possible in metastatic melanoma patients. Compared to matched stool and saliva samples, the absolute concentration of cfmDNA is low but significantly above the levels detected from negative controls. The microbial community of plasma is strongly influenced by laboratory and reagent contaminants introduced during the DNA extraction and sequencing processes. Through the application of an in silico decontamination strategy including the filtering of amplicon sequence variants (ASVs) with batch dependent abundances and those with a higher prevalence in negative controls, we identify known gut commensal bacteria, such as Faecalibacterium, Bacteroides and Ruminococcus, and also other uncharacterised ASVs. We analyse additional plasma samples, highlighting the potential of this framework to identify differences in cfmDNA between healthy and cancer patients. CONCLUSIONS Together, these observations indicate that plasma can harbour a low yet detectable level of cfmDNA. The results highlight the importance of accounting for contamination and provide an analytical decontamination framework to allow the accurate detection of cfmDNA for future biomarker studies in cancer and other diseases.
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Affiliation(s)
| | - Stephen Q. Wong
- Peter MacCallum Cancer Centre, Melbourne, Australia
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia
| | | | | | - Sarah Ftouni
- Peter MacCallum Cancer Centre, Melbourne, Australia
| | - Anthony T. Papenfuss
- Peter MacCallum Cancer Centre, Melbourne, Australia
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia
- Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
- Department of Medical Biology, University of Melbourne, Melbourne, Australia
| | - Shahneen Sandhu
- Peter MacCallum Cancer Centre, Melbourne, Australia
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia
| | - Mark A. Dawson
- Peter MacCallum Cancer Centre, Melbourne, Australia
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia
- Centre for Cancer Research, University of Melbourne, Melbourne, Australia
| | - Sarah-Jane Dawson
- Peter MacCallum Cancer Centre, Melbourne, Australia
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia
- Centre for Cancer Research, University of Melbourne, Melbourne, Australia
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Langner CA, Brenchley JM. FRugally Optimized DNA Octomer (FRODO) qPCR Measurement of HIV and SIV in Human and Nonhuman Primate Samples. Curr Protoc 2021; 1:e93. [PMID: 33861500 DOI: 10.1002/cpz1.93] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Quantitative polymerase chain reactions (qPCRs) are commonly employed to enumerate genes of interest among particular biological samples. Insertion of PCR amplicons into plasmid DNA is a mainstay for creation of known quantities of target sequences to standardize qPCRs. Typically, one amplicon is inserted into one plasmid construct, and the plasmid is then amplified, purified, serially diluted, and quantified to be used to enumerate target sequences in unknown samples. As qPCR is often used to detect multiple amplicons simultaneously, individual qPCR standards are often desired to normalize one to another. Here we report a single plasmid containing eight amplicons, which can be used to quantify several different strains of simian immunodeficiency virus and human immunodeficiency virus, cell number equivalents for humans and nonhuman primates, T cell receptor excision circles, and bacterial 16S DNA. This FRugally Optimized DNA Octomer (FRODO) plasmid was created and standardized to quantify all eight PCR amplicons. © 2021 US Government. Basic Protocol 1: Total genomic DNA extraction from primary cells Basic Protocol 2: Quantitative PCR for viral, bacterial, and cell number equivalents Support Protocol: Purification, quantification, and storage of FRODO standard plasmid DNA.
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Affiliation(s)
- Charlotte A Langner
- Barrier Immunity Section, Laboratory of Viral Diseases, National Institutes of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland
| | - Jason M Brenchley
- Barrier Immunity Section, Laboratory of Viral Diseases, National Institutes of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland
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45
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Merlini E, Cozzi-Lepri A, Castagna A, Costantini A, Caputo SL, Carrara S, Quiros-Roldan E, Ursitti MA, Antinori A, D'Arminio Monforte A, Marchetti G. Inflammation and microbial translocation measured prior to combination antiretroviral therapy (cART) and long-term probability of clinical progression in people living with HIV. BMC Infect Dis 2021; 21:557. [PMID: 34116650 PMCID: PMC8196504 DOI: 10.1186/s12879-021-06260-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Accepted: 05/28/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Despite the effectiveness of cART, people living with HIV still experience an increased risk of serious non-AIDS events, as compared to the HIV negative population. Whether pre-cART microbial translocation (MT) and systemic inflammation might predict morbidity/mortality during suppressive cART, independently of other known risk factors, is still unclear. Thus, we aimed to investigate the role of pre-cART inflammation and MT as predictors of clinical progression in HIV+ patients enrolled in the Icona Foundation Study Cohort. METHODS We included Icona patients with ≥2 vials of plasma stored within 6 months before cART initiation and at least one CD4 count after therapy available. Circulating biomarker: LPS, sCD14, EndoCab, hs-CRP. Kaplan-Meier curves and Cox regression models were used. We defined the endpoint of clinical progression as the occurrence of a new AIDS-defining condition, severe non-AIDS condition (SNAEs) or death whichever occurred first. Follow-up accrued from the data of starting cART and was censored at the time of last available clinical visit. Biomarkers were evaluated as both binary (above/below median) and continuous variables (logescale). RESULTS We studied 486 patients with 125 clinical events: 39 (31%) AIDS, 66 (53%) SNAEs and 20 (16%) deaths. Among the analyzed MT and pro-inflammatory markers, hs-CRP seemed to be the only biomarker retaining some association with the endpoint of clinical progression (i.e. AIDS/SNAEs/death) after adjustment for confounders, both when the study population was stratified according to the median of the distribution (1.51 mg/L) and when the study population was stratified according to the 33% percentiles of the distribution (low 0.0-1.1 mg/L; intermediate 1.2-5.3 mg/L; high > 5.3 mg/L). In particular, the higher the hs-CRP values, the higher the risk of clinical progression (p = 0.056 for median-based model; p = 0.002 for 33% percentile-based model). CONCLUSIONS Our data carries evidence for an association between the risk of disease progression after cART initiation and circulating pre-cART hs-CRP levels but not with levels of MT. These results suggest that pre-therapy HIV-driven pro-inflammatory milieu might overweight MT and its downstream immune-activation.
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Affiliation(s)
- Esther Merlini
- Clinic of Infectious Diseases, Department of Health Sciences, University of Milan, "ASST Santi Paolo e Carlo, Milan, Italy
| | | | - Antonella Castagna
- Department of Infectious Diseases, IRCCS San Raffaele Scientific Institute, University Vita-Salute San Raffael, Milan, Italy
| | - Andrea Costantini
- Clinical Immunology Unit, Azienda Ospedaliero-Universitaria Ospedali Riuniti, Marche Polytechnic University, Ancona, Italy
| | | | - Stefania Carrara
- Microbiology Biobank and Cell Factory Unit, National Institute for Infectious Diseases 'Lazzaro Spallanzani' IRCCS, Rome, Italy
| | - Eugenia Quiros-Roldan
- University Department of Infectious and Tropical Diseases, University of Brescia and ASST Spedali Civili, Brescia, Italy
| | - Maria A Ursitti
- Department of Infectious Diseases, S. Maria Nuova IRCCS Hospital, Reggio Emilia, Italy
| | - Andrea Antinori
- HIV/AIDS Department, INMI, L. Spallanzani, IRCCS, Rome, Italy
| | - Antonella D'Arminio Monforte
- Clinic of Infectious Diseases, Department of Health Sciences, University of Milan, "ASST Santi Paolo e Carlo, Milan, Italy
| | - Giulia Marchetti
- Clinic of Infectious Diseases, Department of Health Sciences, University of Milan, "ASST Santi Paolo e Carlo, Milan, Italy.
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Ribes I, Reus S, Asensio S, García-Ródenas M, León R, Portilla-Tamarit I, Giner L, Portilla J. Inflammatory biomarkers in the pathogenesis of respiratory dysfunction in people living with HIV. Curr HIV Res 2021; 19:384-390. [PMID: 34109914 DOI: 10.2174/1570162x19666210607103157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2020] [Revised: 04/09/2021] [Accepted: 04/12/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND Although the association between HIV infection and airway obstruction is well known, its etiopathogenesis is not clear. OBJECTIVES Our aim was to analyze the association between biomarkers of systemic inflammation and bacterial translocation and pulmonary function tests in HIV-infected patients and compare the results between smokers and non-smokers. METHOD It was a cross-sectional, observational study. The inclusion criterion of the study was people living with HIV with undetectable plasma viral load. The exclusion criterion was other comorbidities associated with systemic inflammation. Outcome variables were spirometry and diffusing capacity for carbon monoxide; explanatory variables were inflammatory biomarkers (interleukin-6, tumor necrosis factor-alpha), bacterial translocation (soluble CD14 [sCD14] and bacterial 16S rDNA), and variables related to HIV infection. Associations were tested using the Pearson/Spearman correlation tests, the Student t-test, and multivariable linear regression. RESULTS We included 71 patients (54.9% smokers). We did not observe significant differences in pulmonary function tests according to biomarkers of inflammation or bacterial translocation. In non-smokers (n=32), sCD14 was negatively correlated with forced expiratory volume in 1 second (R = -0.35, P = 0.048) and forced vital capacity (R= -0.40, P=0.023). Age, time since HIV diagnosis, and CD4+ nadir were associated with alterations in PFTs. In smokers, the only association observed was between the pack-years and pulmonary obstruction. CONCLUSION In non-smokers, HIV patients' lung dysfunction can be, at least partially, related to bacterial translocation (sCD14), CD4+ nadir, and time since HIV diagnosis.
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Affiliation(s)
- Isabel Ribes
- Infectious Diseases Unit, General University Hospital of Alicante, Alicante, Spain
| | - Sergio Reus
- Infectious Diseases Unit, General University Hospital of Alicante, Alicante, Spain
| | - Santos Asensio
- Pneumonology Department, General University Hospital of Alicante, Alicante, Spain
| | - Mar García-Ródenas
- Pneumonology Department, General University Hospital of Alicante, Alicante, Spain
| | - Rafael León
- Infectious Diseases Unit, General University Hospital of Alicante, Alicante, Spain
| | | | - Livia Giner
- Infectious Diseases Unit, General University Hospital of Alicante, Alicante, Spain
| | - Joaquín Portilla
- Infectious Diseases Unit, General University Hospital of Alicante, Alicante, Spain
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Jan AK, Moore JV, Wang RJ, Mcging M, Farr CK, Moisi D, Hartman-Filson M, Kerruish R, Jeon D, Lewis E, Crothers K, Lederman MM, Hunt PW, Huang L. Markers of inflammation and immune activation are associated with lung function in a multi-center cohort of persons with HIV. AIDS 2021; 35:1031-1040. [PMID: 33635847 PMCID: PMC8102352 DOI: 10.1097/qad.0000000000002846] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVES Studies have shown that people with HIV (PWH) may be at increased risk for chronic lung diseases and lung function abnormalities, which may be associated with immune activation. We tested the association of a panel of 12 immune activation and inflammation biomarkers with spirometry and single-breath diffusing capacity for carbon monoxide (DLco). DESIGN Cross-sectional, observational study. METHODS Participants were enrolled from the Inflammation, Aging, Microbes and Obstructive Lung Disease cohort of PWH at two US sites. Biomarkers were examined and standardized spirometry and DLco testing were performed. We tested associations between each biomarker and lung function, examined individually and in combination, using multi-variable linear and logistic regression. RESULTS Among 199 participants, median forced expiratory volume in 1 s (FEV1) was normal (90% predicted) and median DLco was abnormal (69% predicted). The most common lung function abnormality (57%) was a normal FEV1 to forced vital capacity ratio with an abnormal DLco of 80% or less predicted (iso↓DLco). Two markers (IL-6, high-sensitivity C-reactive protein) were associated with FEV1% predicted, whereas eight markers (soluble CD14, soluble CD163, inducible protein-10, soluble CD27, IL-6, soluble tumor necrosis factor receptors 1 and 2, D-dimer) were associated with DLco% predicted. Compared with those participants with normal spirometry and DLco, five markers (soluble CD14, soluble CD163, interferon gamma inducible protein-10, soluble tumor necrosis factor receptors 1 and 2) were associated with iso↓DLco. CONCLUSION Among PWH, different markers of immune activation and inflammation are associated with FEV1% predicted than with DLco% predicted and with an iso↓DLco, representing possible unique pathways of chronic lung disease. Identifying plausible drivers of these inflammatory pathways may clarify mechanisms underlying impaired lung function in HIV infection and may identify therapeutic avenues.
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Affiliation(s)
- Amanda K Jan
- Division of HIV, Infectious Diseases and Global Medicine
| | - Julia V Moore
- Division of HIV, Infectious Diseases and Global Medicine
| | - Richard J Wang
- Division of Pulmonary and Critical Care Medicine, San Francisco General Hospital, University of California, San Francisco, San Francisco, CA
| | - Maggie Mcging
- Division of HIV, Infectious Diseases and Global Medicine
| | - Carly K Farr
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Washington, Seattle, WA
| | - Daniela Moisi
- Division of Infectious Diseases and HIV Medicine, Case Western Reserve University, Cleveland, OH
| | | | - Robert Kerruish
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Washington, Seattle, WA
| | - Diane Jeon
- Division of HIV, Infectious Diseases and Global Medicine
| | - Eula Lewis
- Department of Anesthesia and Perioperative Care, San Francisco General Hospital
| | - Kristina Crothers
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Washington, Seattle, WA
| | - Michael M Lederman
- Division of Infectious Diseases and HIV Medicine, Case Western Reserve University, Cleveland, OH
| | - Peter W Hunt
- Division of Experimental Medicine, San Francisco General Hospital, University of California, San Francisco, San Francisco, CA, USA
| | - Laurence Huang
- Division of HIV, Infectious Diseases and Global Medicine
- Division of Pulmonary and Critical Care Medicine, San Francisco General Hospital, University of California, San Francisco, San Francisco, CA
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Handoko R, Colby DJ, Kroon E, Sacdalan C, de Souza M, Pinyakorn S, Prueksakaew P, Munkong C, Ubolyam S, Akapirat S, Chiarella J, Krebs S, Sereti I, Valcour V, Paul R, Michael NL, Phanuphak N, Ananworanich J, Spudich S. Determinants of suboptimal CD4 + T cell recovery after antiretroviral therapy initiation in a prospective cohort of acute HIV-1 infection. J Int AIDS Soc 2021; 23:e25585. [PMID: 32949118 PMCID: PMC7507109 DOI: 10.1002/jia2.25585] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Revised: 06/18/2020] [Accepted: 07/01/2020] [Indexed: 01/19/2023] Open
Abstract
Introduction Up to 30% of individuals treated with antiretroviral therapy (ART) during chronic HIV fail to recover CD4 counts to >500 cells/mm3 despite plasma viral suppression. We investigated the frequency and associations of suboptimal CD4 recovery after ART started during acute HIV infection (AHI). Methods Participants who started ART in Fiebig I to V AHI with ≥48 weeks of continuous documented HIV‐RNA < 50 copies/mL were stratified by CD4 count at latest study visit to suboptimal immune recovery (SIR; CD4 < 350 cells/mm3), intermediate immune recovery (IIR; 350 ≤ CD4 < 500) and complete immune recovery (CIR; CD4 ≥ 500). Clinical and laboratory parameters were assessed at pre‐ART baseline and latest study visit. Additional inflammatory and neurobehavioral endpoints were examined at baseline and 96 weeks. Results Of 304 participants (96% male, median 26 years old) evaluated after median 144 (range 60 to 420) weeks of ART initiated at median 19 days (range 1 to 62) post‐exposure, 3.6% (n = 11) had SIR and 14.5% (n = 44) had IIR. Pre‐ART CD4 count in SIR compared to CIR participants was 265 versus 411 cells/mm3 (p = 0.002). Individuals with SIR or IIR had a slower CD4 rate of recovery compared to those with CIR. Timing of ART initiation by Fiebig stage did not affect CD4 count during treatment. Following ART, the CD8+T cell count (p = 0.001) and CD4/CD8 ratio (p = 0.047) were lower in SIR compared to CIR participants. Compared to the CIR group at week 96, the combined SIR and IIR groups had higher sCD14 (p = 0.008) and lower IL‐6 (p = 0.04) in plasma, without differences in neuropsychological or psychiatric indices. Conclusions Despite immediate and sustained treatment in AHI, suboptimal CD4 recovery occurs uncommonly and is associated with low pre‐ART CD4 count as well as persistent low CD8 count and CD4/CD8 ratio during treatment.
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Affiliation(s)
| | - Donn J Colby
- SEARCH, The Thai Red Cross AIDS Research Centre, Bangkok, Thailand.,United States Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, USA
| | - Eugène Kroon
- SEARCH, The Thai Red Cross AIDS Research Centre, Bangkok, Thailand
| | - Carlo Sacdalan
- SEARCH, The Thai Red Cross AIDS Research Centre, Bangkok, Thailand
| | - Mark de Souza
- SEARCH, The Thai Red Cross AIDS Research Centre, Bangkok, Thailand
| | - Suteeraporn Pinyakorn
- SEARCH, The Thai Red Cross AIDS Research Centre, Bangkok, Thailand.,United States Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, USA.,The Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA
| | | | | | | | - Siriwat Akapirat
- Armed Forces Research Institute of Medical Sciences, US Army Medical Directorate, Bangkok, Thailand
| | | | - Shelly Krebs
- United States Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, USA.,The Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA
| | - Irini Sereti
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Victor Valcour
- Memory and Aging Center, Department of Neurology, University of California San Francisco, San Francisco, CA, USA
| | - Robert Paul
- Missouri Institute of Mental Health, University of Missouri-St. Louis, St. Louis, MO, USA
| | - Nelson L Michael
- United States Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, USA
| | | | - Jintanat Ananworanich
- SEARCH, The Thai Red Cross AIDS Research Centre, Bangkok, Thailand.,United States Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, USA.,The Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA
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Bifidobacterium breve BBG-001 and intestinal barrier function in preterm babies: Exploratory Studies from the PiPS Trial. Pediatr Res 2021; 89:1818-1824. [PMID: 32947603 DOI: 10.1038/s41390-020-01135-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 08/09/2020] [Accepted: 08/11/2020] [Indexed: 01/17/2023]
Abstract
BACKGROUND Uncertainty remains about the role of probiotics to prevent necrotising enterocolitis (NEC) some of which arises from the variety of probiotic interventions used in different trials, many with no prior evidence of potential efficacy. Mechanistic studies of intestinal barrier function embedded in a large probiotic trial could provide evidence about which properties of probiotics might be important for NEC prevention thus facilitating identification of strains with therapeutic potential. METHODS Intestinal permeability, stool microbiota, SCFAs and mucosal inflammation were assessed from the second postnatal week in babies enrolled to a randomised controlled trial of B. breve BBG-001 (the PiPS trial). Results were compared by allocation and by stool colonisation with the probiotic. RESULTS Ninety-four preterm babies were recruited across six nested studies. B. breve BBG-001 content was higher by allocation and colonisation; Enterobacteriaceae and acetic acid levels were higher by colonisation. No measure of intestinal barrier function showed differences. The PiPS trial found no evidence of efficacy to reduce NEC. CONCLUSIONS That the negative results of the PiPS trial were associated with failure of this probiotic to modify intestinal barrier function supports the possibility that the tests described here have the potential to identify strains to progress to large clinical trials. IMPACT Uncertainty about the therapeutic role of probiotics to prevent necrotising enterocolitis is in part due to the wide range of bacterial strains with no previous evidence of efficacy used in clinical trials. We hypothesised that mechanistic studies embedded in a probiotic trial would provide evidence about which properties of probiotics might be important for NEC prevention. The finding that the probiotic strain tested, Bifidobacterium breve BBG-001, showed neither effects on intestinal barrier function nor clinical efficacy supports the possibility that these tests have the potential to identify strains to progress to large clinical trials.
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50
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Lu L, Wang J, Yang Q, Xie X, Huang Y. The role of CD38 in HIV infection. AIDS Res Ther 2021; 18:11. [PMID: 33820568 PMCID: PMC8021004 DOI: 10.1186/s12981-021-00330-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2020] [Accepted: 03/06/2021] [Indexed: 11/24/2022] Open
Abstract
The widely-expressed molecule CD38 is a single-stranded type II transmembrane glycoprotein that is mainly involved in regulating the differentiation and activation state of the cell. CD38 has broad and complex functions, including enzymatic activity, intercellular signal transduction, cell activation, cytokine production, receptor function and adhesion activity, and it plays an important role in the physiological and pathological processes of many diseases. Many studies have shown that CD38 is related to the occurrence and development of HIV infection, and CD38 may regulate its progression through different mechanisms. Therefore, investigating the role of CD38 in HIV infection and the potential signaling pathways that are involved may provide a new perspective on potential treatments for HIV infection. In the present review, the current understanding of the roles CD38 plays in HIV infection are summarized. In addition, the specific role of CD38 in the process of HIV infection of human CD4+ T lymphocytes is also discussed.
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