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1
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Ao Y, Lan Q, Yu T, Wang Z, Zhang J. Cellular senescence-associated genes in rheumatoid arthritis: Identification and functional analysis. PLoS One 2025; 20:e0317364. [PMID: 39820552 PMCID: PMC11737674 DOI: 10.1371/journal.pone.0317364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Accepted: 12/26/2024] [Indexed: 01/19/2025] Open
Abstract
Rheumatoid arthritis (RA), a long-term autoinflammatory condition causing joint damage and deformities, involves a multifaceted pathogenesis with genetic, epigenetic, and immune factors, including early immune aging. However, its precise cause remains elusive. Cellular senescence, a hallmark of aging marked by a permanent halt in cell division due to damage and stress, is crucial in aging and related diseases. In our study, we analyzed RA microarray data from the Gene Expression Omnibus (GEO) and focused on cellular senescence genes from the CellAge database. We started by selecting five RA datasets from GEO. Next, we pinpointed 29 differentially expressed genes (DEGs) linked to cellular senescence in RA, aligning them with genes from CellAge. We explored the roles of these DEGs in cellular senescence through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. We then pinpointed three key genes (DHX9, CYR61, and ITGB) using random forest and LASSO Cox regression machine learning techniques. An integrated diagnostic model was created using these genes. We also examined the variance in immune cell infiltration and immune checkpoint gene expression between RA and normal samples. Our methodology's predictive accuracy was confirmed in external validation cohorts. Subsequently, RA samples were classified into three distinct subgroups based on the cellular senescence-associated DEGs, and we compared their immune landscapes. Our findings reveal a significant impact of cellular senescence-related DEGs on immune cell infiltration in RA samples. Hence, a deeper understanding of cellular senescence in RA could offer new perspectives for diagnosis and treatment.
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Affiliation(s)
- You Ao
- Department of Orthopaedics, The Fifth Hospital of Harbin, Harbin, Heilongjiang, P. R. China
| | - Qing Lan
- Department of Orthopaedics, The Fifth Hospital of Harbin, Harbin, Heilongjiang, P. R. China
| | - Tianhua Yu
- Department of Orthopaedics, The Fifth Hospital of Harbin, Harbin, Heilongjiang, P. R. China
| | - Zhichao Wang
- Department of Orthopaedics, The Fifth Hospital of Harbin, Harbin, Heilongjiang, P. R. China
| | - Jing Zhang
- Department of Orthopaedics, The Fifth Hospital of Harbin, Harbin, Heilongjiang, P. R. China
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2
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Szymańska B, Knysz B, Ciepłucha H, Piwowar A. Assessment of Metabolic, Inflammatory, and Immunological Disorders Using a New Panel of Plasma Parameters in People Living with HIV Undergoing Antiretroviral Therapy-A Retrospective Study. J Clin Med 2024; 13:4580. [PMID: 39124846 PMCID: PMC11312710 DOI: 10.3390/jcm13154580] [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: 05/28/2024] [Revised: 07/31/2024] [Accepted: 08/01/2024] [Indexed: 08/12/2024] Open
Abstract
Background/Objectives: People living with HIV (PLWH) treated with combined antiretroviral therapy (cART) show a greater predisposition to metabolic and inflammatory disturbances compared to the general population. This study aimed to assess the effect of five years of cART use on the level of selected parameters related to carbohydrate and lipid metabolism and inflammation in PLWH compared to the uninfected. Methods: The levels of sirtuins (-1, -3, -6); irisin (IRS); myostatin (MSTN); peptide YY (PYY); glucagon-like peptide-1 (GLP-1); dipeptidyl peptidase IV (DPP-4); fetuin-A (FETU-A); pentraxin 3 (PTX3); chemokine stromal cell-derived factor 1 (SDF-1); regulated on activation, normal T cell expressed and presumably secreted (RANTES); and interleukins (-4, -7, -15) in the plasma of PLWH and a control group were evaluated by immunoassay methods. The results obtained after five years of antiretroviral therapy were compared with the levels obtained before and one year after cART. Results: Analysis of the parameters after five years of cART showed significantly higher levels in PLWH compared to the control group for SIRT-6, IRS, and IL-4 and significantly lower levels for RANTES and IL-7. There were significantly higher levels of SIRT-6, PYY, GLP-1, and PTX3 obtained after five years of cART compared to the results before therapy and after one year of cART. Conclusions: The results indicated changes occur in the expression of selected parameters during cART use in PLWH. Further research on the clinical usefulness of selected parameters and obtaining new information on the development of HIV-related comorbidities needs to be conducted.
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Affiliation(s)
- Beata Szymańska
- Department of Toxicology, Faculty of Pharmacy, Wroclaw Medical University, 50-556 Wroclaw, Poland;
| | - Brygida Knysz
- Department of Infectious Diseases, Liver Diseases and Acquired Immune Deficiencies, Faculty of Medicine, Wroclaw Medical University, 51-149 Wroclaw, Poland; (B.K.); (H.C.)
| | - Hubert Ciepłucha
- Department of Infectious Diseases, Liver Diseases and Acquired Immune Deficiencies, Faculty of Medicine, Wroclaw Medical University, 51-149 Wroclaw, Poland; (B.K.); (H.C.)
| | - Agnieszka Piwowar
- Department of Toxicology, Faculty of Pharmacy, Wroclaw Medical University, 50-556 Wroclaw, Poland;
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3
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Love M, Behrens-Bradley N, Ahmad A, Wertheimer A, Klotz S, Ahmad N. Plasma Levels of Secreted Cytokines in Virologically Controlled HIV-Infected Aging Adult Individuals on Long-Term Antiretroviral Therapy. Viral Immunol 2024; 37:202-215. [PMID: 38717822 PMCID: PMC11238844 DOI: 10.1089/vim.2023.0123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/14/2024] Open
Abstract
HIV-infected (HIV+) aging adult individuals who have achieved undetectable viral load and improved CD4 T cell counts due to long-term antiretroviral therapy (ART) may continue to experience inflammation and immunosenescence. Therefore, we evaluated the plasma levels of proinflammatory and anti-inflammatory cytokines in 173 HIV+ aging adult individuals with age ranging from 22 to 81 years on long-term ART with viral load mostly <20 HIV RNA copies/mL and compared with 92 HIV-uninfected (HIV- or healthy controls) aging individuals. We found that the median levels of TNF-α, IFN-γ, IL-1β, IL-6, and IL-10 were higher (p < 0.001 to <0.0001) and IL-17 trended lower in HIV+ individuals than healthy controls. Increasing CD4 T cell counts in the HIV+ cohort did not significantly change the circulating cytokine levels, although levels of IL-1β increased. However, IL-17 levels significantly decreased with increasing CD4 counts in the healthy controls and yet unchanged in the HIV+ cohort. Of note, the levels of circulating IL-17 were significantly reduced comparatively in the healthy controls where the CD4 count was below 500, yet once above 500 the levels of CD4, IL-17 levels were comparable with the HIV+ cohort. With increasing CD8 T cell counts, the levels of these cytokines were not significantly altered, although levels of TNF-α, IFN-γ, and IL-6 declined, whereas IL-1β and IL-17 were slightly elevated. Furthermore, increasing age of the HIV+ cohort did not significantly impact the cytokine levels although a slight increase in TNF-α, IL-6, IL-10, and IL-17 was observed. Similarly, these cytokines were not significantly modulated with increasing levels of undetectable viral loads, whereas some of the HIV+ individuals had higher levels of TNF-α, IFN-γ, and IL-1β. In summary, our findings show that HIV+ aging adult individuals with undetectable viral load and restored CD4 T cell counts due to long-term ART still produce higher levels of both proinflammatory and anti-inflammatory cytokines compared with healthy controls, suggesting some level of inflammation.
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Affiliation(s)
- Maria Love
- Department of Immunobiology, University of Arizona, Tucson, Arizona, USA
| | | | - Aasim Ahmad
- Department of Immunobiology, University of Arizona, Tucson, Arizona, USA
| | - Anne Wertheimer
- Department of Medicine, College of Medicine, University of Arizona, Tucson, Arizona, USA
- Department of BIO5 Institute, University of Arizona, Tucson, Arizona, USA
| | - Stephen Klotz
- Department of Medicine, College of Medicine, University of Arizona, Tucson, Arizona, USA
| | - Nafees Ahmad
- Department of Immunobiology, University of Arizona, Tucson, Arizona, USA
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4
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Dinges SS, Amini K, Notarangelo LD, Delmonte OM. Primary and secondary defects of the thymus. Immunol Rev 2024; 322:178-211. [PMID: 38228406 PMCID: PMC10950553 DOI: 10.1111/imr.13306] [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] [Indexed: 01/18/2024]
Abstract
The thymus is the primary site of T-cell development, enabling generation, and selection of a diverse repertoire of T cells that recognize non-self, whilst remaining tolerant to self- antigens. Severe congenital disorders of thymic development (athymia) can be fatal if left untreated due to infections, and thymic tissue implantation is the only cure. While newborn screening for severe combined immune deficiency has allowed improved detection at birth of congenital athymia, thymic disorders acquired later in life are still underrecognized and assessing the quality of thymic function in such conditions remains a challenge. The thymus is sensitive to injury elicited from a variety of endogenous and exogenous factors, and its self-renewal capacity decreases with age. Secondary and age-related forms of thymic dysfunction may lead to an increased risk of infections, malignancy, and autoimmunity. Promising results have been obtained in preclinical models and clinical trials upon administration of soluble factors promoting thymic regeneration, but to date no therapy is approved for clinical use. In this review we provide a background on thymus development, function, and age-related involution. We discuss disease mechanisms, diagnostic, and therapeutic approaches for primary and secondary thymic defects.
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Affiliation(s)
- Sarah S. Dinges
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
- Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Kayla Amini
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Luigi D. Notarangelo
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Ottavia M. Delmonte
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
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5
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Mechanisms of immune aging in HIV. Clin Sci (Lond) 2022; 136:61-80. [PMID: 34985109 DOI: 10.1042/cs20210344] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 12/13/2021] [Accepted: 12/14/2021] [Indexed: 12/11/2022]
Abstract
Massive CD4+ T-cell depletion as well as sustained immune activation and inflammation are hallmarks of Human Immunodeficiency Virus (HIV)-1 infection. In recent years, an emerging concept draws an intriguing parallel between HIV-1 infection and aging. Indeed, many of the alterations that affect innate and adaptive immune subsets in HIV-infected individuals are reminiscent of the process of immune aging, characteristic of old age. These changes, of which the presumed cause is the systemic immune activation established in patients, likely participate in the immuno-incompetence described with HIV progression. With the success of antiretroviral therapy (ART), HIV-seropositive patients can now live for many years despite chronic viral infection. However, acquired immunodeficiency syndrome (AIDS)-related opportunistic infections have given way to chronic diseases as the leading cause of death since HIV infection. Therefore, the comparison between HIV-1 infected patients and uninfected elderly individuals goes beyond the sole onset of immunosenescence and extends to the deterioration of several physiological functions related to inflammation and systemic aging. In light of this observation, it is interesting to understand the precise link between immune activation and aging in HIV-1 infection to figure out how to best care for people living with HIV (PLWH).
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6
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Min J, Jo H, Chung YJ, Song JY, Kim MJ, Kim MR. Vitamin D and the Immune System in Menopause: A Review. J Menopausal Med 2022; 27:109-114. [PMID: 34989184 PMCID: PMC8738846 DOI: 10.6118/jmm.21011] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 08/31/2021] [Accepted: 10/26/2021] [Indexed: 12/18/2022] Open
Abstract
Menopause is a normal phenomenon in a woman’s life cycle involving multiple health-related issues that contribute to physical instability. Changes in the immune system in postmenopausal women are caused by estrogen deprivation along with age. Increased proinflammatory serum marker levels, cytokine responses in body cells, decreased CD4 T and B lymphocyte levels, and natural killer cell cytotoxic activity are also observed during postmenopause. Moreover, vitamin D, in addition to its classical effects on calcium homeostasis and bone density, plays an important role. Current evidence indicates that vitamin D regulates innate and adaptive immune responses; however, vitamin D deficiency is linked to increased autoimmune activity and infection susceptibility. This review provides an overview of the consequences of immune alterations as an outcome of aging in postmenopausal women and the benefit of vitamin D supplementation.
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Affiliation(s)
- Jaeyoung Min
- Department of Obstetrics and Gynecology, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Hagyeong Jo
- Department of Obstetrics and Gynecology, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Youn-Jee Chung
- Department of Obstetrics and Gynecology, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jae Yen Song
- Department of Obstetrics and Gynecology, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Min Jeong Kim
- Department of Obstetrics and Gynecology, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Mee-Ran Kim
- Department of Obstetrics and Gynecology, College of Medicine, The Catholic University of Korea, Seoul, Korea.
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7
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Goldstein RH, Mehan WA, Hutchison B, Robbins GK. Case 24-2021: A 63-Year-Old Woman with Fever, Sore Throat, and Confusion. N Engl J Med 2021; 385:641-648. [PMID: 34379926 DOI: 10.1056/nejmcpc2107345] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Affiliation(s)
- Robert H Goldstein
- From the Departments of Medicine (R.H.G., G.K.R.), Radiology (W.A.M.), and Pathology (B.H.), Massachusetts General Hospital, and the Departments of Medicine (R.H.G., G.K.R.), Radiology (W.A.M.), and Pathology (B.H.), Harvard Medical School - both in Boston
| | - William A Mehan
- From the Departments of Medicine (R.H.G., G.K.R.), Radiology (W.A.M.), and Pathology (B.H.), Massachusetts General Hospital, and the Departments of Medicine (R.H.G., G.K.R.), Radiology (W.A.M.), and Pathology (B.H.), Harvard Medical School - both in Boston
| | - Bailey Hutchison
- From the Departments of Medicine (R.H.G., G.K.R.), Radiology (W.A.M.), and Pathology (B.H.), Massachusetts General Hospital, and the Departments of Medicine (R.H.G., G.K.R.), Radiology (W.A.M.), and Pathology (B.H.), Harvard Medical School - both in Boston
| | - Gregory K Robbins
- From the Departments of Medicine (R.H.G., G.K.R.), Radiology (W.A.M.), and Pathology (B.H.), Massachusetts General Hospital, and the Departments of Medicine (R.H.G., G.K.R.), Radiology (W.A.M.), and Pathology (B.H.), Harvard Medical School - both in Boston
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8
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Obesity, Vascular Disease and Frailty in Aging Women with HIV. ACTA ACUST UNITED AC 2021; 3. [PMID: 34368807 PMCID: PMC8345026 DOI: 10.20900/agmr20210014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Women with chronic HIV infection (WWH) living in the United States,
experience a disproportionately high rate of obesity compared to uninfected
populations. Both overweight and obesity, particularly central obesity, are
major contributors to insulin resistance, hypertension, and
dyslipidemia—the major components of metabolic syndromes, including type
2 diabetes, and leading to increased cardiovascular risk, including coronary
heart disease, and cerebrovascular diseases. Notably, declining physical
performance and frailty co-occur with vascular morbidities as well as changes in
bone. These factors tend to exacerbate each other and accelerate the aging
trajectory, leading to poorer quality of life, cognitive impairments, dementia,
and eventually, death. In WWH, persistent HIV infection, sustained treatment for
HIV infection, and concomitant obesity, may accelerate aging-related morbidities
and poorer aging outcomes. Furthermore, health disparities factors common among
some WWH, are independently associated with obesity and higher vascular risk.
The purpose of this review is to describe the constellation of obesity, cardio-
and cerebrovascular diseases, bone health and frailty among aging WWH, a 21st
century emergence.
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9
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Behrens NE, Love M, Bandlamuri M, Bernhardt D, Wertheimer A, Klotz SA, Ahmad N. Characterization of HIV-1 Envelope V3 Region Sequences from Virologically Controlled HIV-Infected Older Patients on Long Term Antiretroviral Therapy. AIDS Res Hum Retroviruses 2021; 37:233-245. [PMID: 33287636 DOI: 10.1089/aid.2020.0139] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Although many HIV-infected patients have attained older age owing to the success of antiretroviral therapy (ART) in controlling viremia and increasing CD4 T cell counts, HIV continues to persist in several target cells. We have characterized 514 HIV-1 envelope V3 region sequences (94-96 amino acids [aa]) from 25 HIV-infected older patients' peripheral blood mononuclear cell DNA on long-term ART with controlled viremia (undetectable viral load) and improved CD4 T cell counts. Phylogenetic analysis revealed that the V3 region sequences of each patient formed distinct clusters that were well separated and discriminated from other patients' sequences. The coding potential of the V3 region, including several patient-specific amino acid motifs and functional domains, including the two cysteines sandwiching the V3 loop, the central GPGR motif with variation at one position in some sequences, the base GDIR motif, and the N-glycosylation sites were generally conserved. The patients' V3 region sequences contained amino acid motifs conferring affinity mostly for CCR5 coreceptor, suggesting R5 phenotype. There was a low degree of heterogeneity and lower estimates of genetic diversity in all 25 patients' V3 region sequences. Twelve of 25 patients' V3 region sequences were found to be under positive selection pressure. Analysis of the several cytotoxic T lymphocytes (CTL) epitopes showed variation, whereas some of known neutralizing antibodies (nAbs) epitopes showed conservation in patients' V3 region sequences. In conclusion, a low degree of genetic variability and maintenance of functional domains with R5 phenotypes, and variation in CTL and conservation of nAb epitopes were the hallmarks of V3 region sequences from our 25 virologically controlled HIV-infected older patients on long-term ART.
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Affiliation(s)
- Nicole E. Behrens
- Department of Immunobiology, College of Medicine, University of Arizona, Tucson, Arizona, USA
| | - Maria Love
- Department of Immunobiology, College of Medicine, University of Arizona, Tucson, Arizona, USA
| | - Meghana Bandlamuri
- Department of Immunobiology, College of Medicine, University of Arizona, Tucson, Arizona, USA
| | - Dana Bernhardt
- Department of Immunobiology, College of Medicine, University of Arizona, Tucson, Arizona, USA
| | - Anne Wertheimer
- Department of Medicine, College of Medicine, University of Arizona, Tucson, Arizona, USA
- BIO5 Institute, University of Arizona, Tucson, Arizona, USA
| | - Stephen A. Klotz
- Department of Medicine, College of Medicine, University of Arizona, Tucson, Arizona, USA
| | - Nafees Ahmad
- Department of Immunobiology, College of Medicine, University of Arizona, Tucson, Arizona, USA
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10
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Abstract
Following periods of haematopoietic cell stress, such as after chemotherapy, radiotherapy, infection and transplantation, patient outcomes are linked to the degree of immune reconstitution, specifically of T cells. Delayed or defective recovery of the T cell pool has significant clinical consequences, including prolonged immunosuppression, poor vaccine responses and increased risks of infections and malignancies. Thus, strategies that restore thymic function and enhance T cell reconstitution can provide considerable benefit to individuals whose immune system has been decimated in various settings. In this Review, we focus on the causes and consequences of impaired adaptive immunity and discuss therapeutic strategies that can recover immune function, with a particular emphasis on approaches that can promote a diverse repertoire of T cells through de novo T cell formation.
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11
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Increasing age is associated with elevated circulating interleukin-6 and enhanced temporal summation of mechanical pain in people living with HIV and chronic pain. Pain Rep 2020. [DOI: 10.1097/pr9.0000000000000859] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
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Perez MD, Seu L, Lowman KE, Moylan DC, Tidwell C, Samuel S, Duverger A, Wagner FH, Carlin E, Sharma V, Pope B, Raman C, Erdmann N, Locke J, Hu H, Sabbaj S, Kutsch O. The tetraspanin CD151 marks a unique population of activated human T cells. Sci Rep 2020; 10:15748. [PMID: 32978478 PMCID: PMC7519159 DOI: 10.1038/s41598-020-72719-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Accepted: 09/04/2020] [Indexed: 02/06/2023] Open
Abstract
Tetraspanins are a family of proteins with an array of functions that are well studied in cancer biology, but their importance in immunology is underappreciated. Here we establish the tetraspanin CD151 as a unique marker of T-cell activation and, in extension, an indicator of elevated, systemic T-cell activity. Baseline CD151 expression found on a subset of T-cells was indicative of increased activation of the MAPK pathway. Following TCR/CD3 activation, CD151 expression was upregulated on the overall T-cell population, a quintessential feature of an activation marker. CD151+ T-cell frequencies in the spleen, an organ with increased immune activity, were twice as high as in paired peripheral blood samples. This CD151+ T-cell frequency increase was not paralleled by an increase of CD25 or CD38, demonstrating that CD151 expression is regulated independently of other T-cell activation markers. CD151+ T-cells were also more likely to express preformed granzyme B, suggesting that CD151+ T cells are pro-inflammatory. To this end, HIV-1 patients on antiretroviral therapy who are reported to exhibit chronically elevated levels of immune activity, had significantly higher CD4+CD151+ T-cell frequencies than healthy controls, raising the possibility that proinflammatory CD151+ T cells could contribute to the premature immunological aging phenotype observed in these patients.
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Affiliation(s)
- Mildred D Perez
- Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL, USA
| | - Lillian Seu
- Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL, USA
| | - Kelsey E Lowman
- Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL, USA
| | - David C Moylan
- Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL, USA
| | - Christopher Tidwell
- Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL, USA
| | - Shekwonya Samuel
- Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL, USA
| | - Alexandra Duverger
- Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL, USA
| | - Frederic H Wagner
- Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL, USA
| | - Eric Carlin
- Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL, USA
| | - Vishal Sharma
- Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL, USA
| | - Brandon Pope
- Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL, USA
| | - Chander Raman
- Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL, USA
| | - Nathan Erdmann
- Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL, USA
| | - Jayme Locke
- Department of Surgery, The University of Alabama at Birmingham, Birmingham, AL, USA
| | - Hui Hu
- Department of Microbiology, The University of Alabama at Birmingham, Birmingham, AL, USA
| | - Steffanie Sabbaj
- Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL, USA.
| | - Olaf Kutsch
- Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL, USA.
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Tsutsumi T, Sato H, Kikuchi T, Ikeuchi K, Lim LA, Adachi E, Koga M, Okushin K, Kawahara T, Koibuchi T, Yotsuyanagi H. Factors associated with clearance of hepatitis B virus surface antigen in patients infected with human immunodeficiency virus. Medicine (Baltimore) 2020; 99:e21271. [PMID: 32702915 PMCID: PMC7373618 DOI: 10.1097/md.0000000000021271] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Owing to similar routes of transmission, hepatitis B virus (HBV) and human immunodeficiency virus (HIV) coinfection commonly occurs. Compared with patients infected with only HBV, coinfected patients develop persistent HBV infection followed by advanced liver diseases. However, the characteristics of HIV-infected patients who can achieve the clearance of HBV surface antigen (HBsAg) have not been clarified. In this study, we retrospectively examined patients coinfected with HBV and HIV and determined the host factors associated with HBsAg clearance.Among HIV-infected patients who visited our hospital between 1994 and 2017, we examined medical records of those who were seropositive for HBsAg at least once. Among them, patients who cleared HBsAg afterward were regarded as "cured," while those who remained HBsAg-seropositive until 2017 were "chronic."HBsAg seropositivity was found in 57 patients, and among them, 27 male patients were cured whereas 18 were chronic. The cured patients were significantly younger and had higher CD4 cell and platelet counts than the chronic patients. In addition, the cured patients had higher levels of transaminases after the detection of HBsAg. Multivariate analysis revealed age as an independent factor. Analyses of the patients infected with genotype A also showed that the cured patients had significantly higher CD4 cell counts.Considering that the CD4 cell and platelet counts were higher in the cured patients, immunological and liver functions were closely associated with HBsAg clearance. Higher levels of transaminases in the cured patients may also reflect the immunological function leading to HBsAg clearance.
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Affiliation(s)
- Takeya Tsutsumi
- Division of Infectious Diseases, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo
| | - Hidenori Sato
- Department of Infectious Diseases and Applied Immunology, IMSUT Hospital of The Institute of Medical Science, The University of Tokyo
| | - Tadashi Kikuchi
- Department of Infectious Diseases and Applied Immunology, IMSUT Hospital of The Institute of Medical Science, The University of Tokyo
| | - Kazuhiko Ikeuchi
- Division of Infectious Diseases, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo
| | - Lay Ahyoung Lim
- Department of Infectious Diseases and Applied Immunology, IMSUT Hospital of The Institute of Medical Science, The University of Tokyo
| | - Eisuke Adachi
- Department of Infectious Diseases and Applied Immunology, IMSUT Hospital of The Institute of Medical Science, The University of Tokyo
| | - Michiko Koga
- Division of Infectious Diseases, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo
| | - Kazuya Okushin
- Department of Infection Control and Prevention, Graduate School of Medicine, The University of Tokyo
| | - Takuya Kawahara
- Central Coordinating Unit, Clinical Research Support Center, The University of Tokyo Hospital, Tokyo, Japan
| | - Tomohiko Koibuchi
- Department of Infectious Diseases and Applied Immunology, IMSUT Hospital of The Institute of Medical Science, The University of Tokyo
| | - Hiroshi Yotsuyanagi
- Division of Infectious Diseases, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo
- Department of Infectious Diseases and Applied Immunology, IMSUT Hospital of The Institute of Medical Science, The University of Tokyo
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Ceccarelli G, Pinacchio C, Santinelli L, Adami PE, Borrazzo C, Cavallari EN, Vullo A, Innocenti GP, Mezzaroma I, Mastroianni CM, d’Ettorre G. Physical Activity and HIV: Effects on Fitness Status, Metabolism, Inflammation and Immune-Activation. AIDS Behav 2020; 24:1042-1050. [PMID: 31016505 DOI: 10.1007/s10461-019-02510-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Several studies evidenced that a sedentary lifestyle is related with higher levels of systemic inflammation and highlighted that physical activity can trigger anti-inflammatory effects. To evaluate the impact of self-prescribed physical activity on fitness status, metabolism, inflammation and immune-activation in people living with HIV, an interim analysis of the results of the clinical trial PRIMO (NCT03392805) was performed. Patients enrolled were divided in 2 groups on the basis of self-prescribed physical activity: a physically active group (self-prescribed physical activity) and a sedentary group. Physical fitness was evaluated by sport medicine specialists and related to nutritional status, anthropometric variables, adipokines levels (adiponectin, leptin, resistin), peripheral immune-activation (CD38, HLA-DR on CD4 and CD8), and plasma inflammatory markers (IL-6 and TNF-α). The physically active group had a better profile in anthropometric measures and aerobic fitness but did not show lower levels of immune-activation compared to sedentary group. Also serum IL-6, TNF-α, and adipokines levels showed no statistical differences. On the basis of these data, a regular self-organized physical activity seems useful to improve cardio-respiratory fitness, but unable to control HIV-related immune-activation.
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15
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Furler RL, Newcombe KL, Del Rio Estrada PM, Reyes-Terán G, Uittenbogaart CH, Nixon DF. Histoarchitectural Deterioration of Lymphoid Tissues in HIV-1 Infection and in Aging. AIDS Res Hum Retroviruses 2019; 35:1148-1159. [PMID: 31474115 DOI: 10.1089/aid.2019.0156] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Impaired immunity is a common symptom of aging and advanced Human Immunodeficiency Virus type 1 (HIV-1) disease. In both diseases, a decline in lymphocytic function and cellularity leads to ineffective adaptive immune responses to opportunistic infections and vaccinations. Furthermore, despite sustained myeloid cellularity there is a background of chronic immune activation and a decrease in innate immune function in aging. In HIV-1 disease, myeloid cellularity is often more skewed than in normal aging, but similar chronic activation and innate immune dysfunction typically arise. Similarities between aging and HIV-1 infection have led to several investigations into HIV-1-mediated aging of the immune system. In this article, we review various studies that report alterations of leukocyte number and function during aging, and compare those alterations with those observed during progressive HIV-1 disease. We pay particular attention to changes within lymphoid tissue microenvironments and how histoarchitectural changes seen in these two diseases affect immunity. As we review various immune compartments including peripheral blood as well as primary and secondary lymphoid organs, common themes arise that help explain the decline of immunity in the elderly and in HIV-1-infected individuals with advanced disease. In both conditions, lymphoid tissues often show signs of histoarchitectural deterioration through fat accumulation and/or fibrosis. These structural changes can be attributed to a loss of communication between leukocytes and the surrounding stromal cells that produce the extracellular matrix components and growth factors necessary for cell migration, cell proliferation, and lymphoid tissue function. Despite the common general impairment of immunity in aging and HIV-1 progression, deterioration of immunity is caused by distinct mechanisms at the cellular and tissue levels in these two diseases.
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Affiliation(s)
- Robert L. Furler
- Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine, New York, New York
| | - Kevin L. Newcombe
- Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine, New York, New York
| | - Perla M. Del Rio Estrada
- Departmento de Investigación en Enfermedades Infecciosas, Instituto Nacional de Enfermedades Respiratorias “Ismael Cosío Villegas,” CDMX, Mexico DF, Mexico
| | - Gustavo Reyes-Terán
- Departmento de Investigación en Enfermedades Infecciosas, Instituto Nacional de Enfermedades Respiratorias “Ismael Cosío Villegas,” CDMX, Mexico DF, Mexico
| | - Christel H. Uittenbogaart
- Department of Microbiology, Immunology and Molecular Genetics, Medicine-Pediatrics, UCLA AIDS Institute and the Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, California
| | - Douglas F. Nixon
- Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine, New York, New York
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16
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Pierre S, Seo G, Rivera VR, Walsh KF, Victor JJ, Charles B, Julmiste G, Dumont E, Apollon A, Cadet M, Saint‐Vil A, Marcelin A, Severe P, Lee MH, Kingery J, Koenig S, Fitzgerald D, Pape J, McNairy ML. Prevalence of hypertension and cardiovascular risk factors among long-term AIDS survivors: A report from the field. J Clin Hypertens (Greenwich) 2019; 21:1558-1566. [PMID: 31448551 PMCID: PMC6896990 DOI: 10.1111/jch.13663] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2019] [Revised: 05/14/2019] [Accepted: 06/18/2019] [Indexed: 12/23/2022]
Abstract
HIV infection is associated with increased risk and progression of cardiovascular disease (CVD), yet little is known about the prevalence of CVD risk factors among long-term AIDS survivors in resource-limited settings. Using routinely collected data, we conducted a retrospective study to describe the prevalence of CVD risk factors among a cohort of HIV-infected patients followed for over 10 years in Port-au Prince, Haiti. This cohort includes 910 adults who initiated antiretroviral therapy (ART) between 2003 and 2004 and remained in care between 2014 and 2016 when routine screening for CVD risk factors was implemented at a large clinic in Haiti. A total of 397 remained in care ≥10 years and received screening. At ART initiation, 59% were female, median age was 38 years (IQR 33-44), and median CD4 count was 117 cells/mm3 (IQR 34-201). Median follow-up time from ART initiation was 12.1 years (IQR 11.7-12.7). At screening, median CD4 count was 574 cells/mm3 (IQR 378-771), and 84% (282 of 336 screened) had HIV-1 RNA < 1000 copies/mL. Seventy-four percent of patients had at least 1 risk factor including 58% (224/385) with hypertension, 8% (24/297) diabetes, 43% (119/275) hypercholesterolemia, 8% (20/248) active smoking, and 10% (25/245) obesity. Factors associated with hypertension were age (adjusted OR 1.06, P < .001) and weight at screening (adjusted OR 1.02, P = .019). Long-term AIDS survivors have a high prevalence of CVD risk factors, primarily hypertension. Integration of cardiovascular screening and management into routine HIV care is needed to maximize health outcomes among aging HIV patients in resource-limited settings.
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Affiliation(s)
- Samuel Pierre
- Haitian Group for the Study of Kaposi's Sarcoma and Opportunistic Infections (GHESKIO)Port‐au‐PrinceHaiti
| | - Grace Seo
- Haitian Group for the Study of Kaposi's Sarcoma and Opportunistic Infections (GHESKIO)Port‐au‐PrinceHaiti
- Department of Medicine, Center for Global HealthWeill Cornell MedicineNew YorkNYUSA
| | - Vanessa R. Rivera
- Haitian Group for the Study of Kaposi's Sarcoma and Opportunistic Infections (GHESKIO)Port‐au‐PrinceHaiti
- Department of Medicine, Center for Global HealthWeill Cornell MedicineNew YorkNYUSA
| | - Kathleen F. Walsh
- Department of Medicine, Center for Global HealthWeill Cornell MedicineNew YorkNYUSA
- Division of General Internal MedicineWeill Cornell MedicineNew YorkNYUSA
| | - Jean Joscar Victor
- Haitian Group for the Study of Kaposi's Sarcoma and Opportunistic Infections (GHESKIO)Port‐au‐PrinceHaiti
| | - Benedict Charles
- Haitian Group for the Study of Kaposi's Sarcoma and Opportunistic Infections (GHESKIO)Port‐au‐PrinceHaiti
| | - Gaetane Julmiste
- Haitian Group for the Study of Kaposi's Sarcoma and Opportunistic Infections (GHESKIO)Port‐au‐PrinceHaiti
| | - Emelyne Dumont
- Haitian Group for the Study of Kaposi's Sarcoma and Opportunistic Infections (GHESKIO)Port‐au‐PrinceHaiti
| | - Alexandra Apollon
- Haitian Group for the Study of Kaposi's Sarcoma and Opportunistic Infections (GHESKIO)Port‐au‐PrinceHaiti
| | - Molene Cadet
- Haitian Group for the Study of Kaposi's Sarcoma and Opportunistic Infections (GHESKIO)Port‐au‐PrinceHaiti
| | - Alix Saint‐Vil
- Haitian Group for the Study of Kaposi's Sarcoma and Opportunistic Infections (GHESKIO)Port‐au‐PrinceHaiti
| | - Adias Marcelin
- Haitian Group for the Study of Kaposi's Sarcoma and Opportunistic Infections (GHESKIO)Port‐au‐PrinceHaiti
| | - Patrice Severe
- Haitian Group for the Study of Kaposi's Sarcoma and Opportunistic Infections (GHESKIO)Port‐au‐PrinceHaiti
| | - Myung Hee Lee
- Department of Medicine, Center for Global HealthWeill Cornell MedicineNew YorkNYUSA
| | - Justin Kingery
- Department of Medicine, Center for Global HealthWeill Cornell MedicineNew YorkNYUSA
- Division of General Internal MedicineWeill Cornell MedicineNew YorkNYUSA
| | - Serena Koenig
- Brigham and Women's HospitalHarvard Medical SchoolBostonMAUSA
| | - Daniel Fitzgerald
- Department of Medicine, Center for Global HealthWeill Cornell MedicineNew YorkNYUSA
| | - Jean Pape
- Haitian Group for the Study of Kaposi's Sarcoma and Opportunistic Infections (GHESKIO)Port‐au‐PrinceHaiti
- Department of Medicine, Center for Global HealthWeill Cornell MedicineNew YorkNYUSA
| | - Margaret L. McNairy
- Department of Medicine, Center for Global HealthWeill Cornell MedicineNew YorkNYUSA
- Division of General Internal MedicineWeill Cornell MedicineNew YorkNYUSA
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17
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Yoshikura H. Shift of HIV/AIDS Deaths to an Older Age and Gender Difference: Inferences Derived from the Vital Statistics of Japan. Jpn J Infect Dis 2019; 72:359-367. [PMID: 31061361 DOI: 10.7883/yoken.jjid.2019.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
From 1995 to 2000, the mortality rates of human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) patients < 54 years of age have declined; however, since 2000, deaths of HIV/AIDS patients aged > 55 have started to increase. Although deaths directly linked to infections have declined since 2005, those related to malignancy, encephalopathy, interstitial pneumonia, wasting syndrome, etc. persisted. In 10 years from 1999-2004 to 2010-2017, the age at death shifted by 5 years towards an older age in the general population and in patients with HIV/AIDS (mainly males), adult T-cell leukemia, or Creutzfeldt-Jakob disease. Among these, HIV/AIDS patients and the general population exhibited an unequivocal gender difference. As of 2011-2016, the median of the deaths of the HIV/AIDS patients was 52.5 years for males and 70 years for females, while the median of the deaths of the general population was 75 years for males and 85 years for females. Hence, male HIV/AIDS patients died 22.5 years earlier and female HIV/AIDS patients 15 years earlier than did the general population. A common denominator of HIV/AIDS-related deaths and deaths among the general population could be CD4+T cells as these cells are primary targets of HIV, and a decline in naïve CD4+T cell count is a hallmark of aging.
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18
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Warren JA, Clutton G, Goonetilleke N. Harnessing CD8 + T Cells Under HIV Antiretroviral Therapy. Front Immunol 2019; 10:291. [PMID: 30863403 PMCID: PMC6400228 DOI: 10.3389/fimmu.2019.00291] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Accepted: 02/04/2019] [Indexed: 12/16/2022] Open
Abstract
Antiretroviral therapy (ART) has transformed HIV from a fatal disease to a chronic condition. In recent years there has been considerable interest in strategies to enable HIV-infected individuals to cease ART without viral rebound, either by purging all cells infected harboring replication-competent virus (HIV eradication), or by boosting immune responses to allow durable suppression of virus without rebound (HIV remission). Both of these approaches may need to harness HIV-specific CD8+ T cells to eliminate infected cells and/or prevent viral spread. In untreated infection, both HIV-specific and total CD8+ T cells are dysfunctional. Here, we review our current understanding of both global and HIV-specific CD8+ T cell immunity in HIV-infected individuals with durably suppressed viral load under ART, and its implications for HIV cure, eradication or remission. Overall, the literature indicates significant normalization of global T cell parameters, including CD4/8 ratio, activation status, and telomere length. Global characteristics of CD8+ T cells from HIV+ART+ individuals align more closely with those of HIV-seronegative individuals than of viremic HIV-infected individuals. However, markers of senescence remain elevated, leading to the hypothesis that immune aging is accelerated in HIV-infected individuals on ART. This phenomenon could have implications for attempts to prime de novo, or boost existing HIV-specific CD8+ T cell responses. A major challenge for both HIV cure and remission strategies is to elicit HIV-specific CD8+ T cell responses superior to that elicited by natural infection in terms of response kinetics, magnitude, breadth, viral suppressive capacity, and tissue localization. Addressing these issues will be critical to the success of HIV cure and remission attempts.
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Affiliation(s)
- Joanna A Warren
- Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC, United States
| | - Genevieve Clutton
- Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC, United States
| | - Nilu Goonetilleke
- Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC, United States.,UNC HIV Cure Center, University of North Carolina, Chapel Hill, NC, United States
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19
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Affiliation(s)
- Sasha A Fahme
- From the Center for Global Health, Weill Cornell Medical College, New York, NY (S.A.F., R.P.)
- Department of Internal Medicine, Weill Bugando School of Medicine, Mwanza, Tanzania (S.A.F., R.P.)
| | - Gerald S Bloomfield
- Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC (G.S.B.)
| | - Robert Peck
- From the Center for Global Health, Weill Cornell Medical College, New York, NY (S.A.F., R.P.)
- Department of Internal Medicine, Weill Bugando School of Medicine, Mwanza, Tanzania (S.A.F., R.P.)
- Mwanza Interventions Trial Unit, Tanzania (R.P.)
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20
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Behrens NE, Wertheimer A, Klotz SA, Ahmad N. Reduction in terminally differentiated T cells in virologically controlled HIV-infected aging patients on long-term antiretroviral therapy. PLoS One 2018; 13:e0199101. [PMID: 29897981 PMCID: PMC5999291 DOI: 10.1371/journal.pone.0199101] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Accepted: 05/31/2018] [Indexed: 12/14/2022] Open
Abstract
Several studies have shown an increased accumulation of terminally differentiated T cells during HIV infection, suggestive of exhaustion/senescence, causing dysregulation of T cell homeostasis and function and rapid HIV disease progression. We have investigated whether long-term antiretroviral therapy (ART), which controls viremia and restores CD4 T cell counts, is correlated with reduction in terminally differentiated T cells, improved ratios of naïve to memory and function of T cells in 100 virologically controlled HIV-infected patients. We show that while the median frequencies of terminally differentiated CD4+ and CD8+ T cells (CD28-, CD27-, CD57+ and CD28-CD57+), were higher in the virologically controlled HIV-infected patients’ cohort compared with uninfected individuals’ cohort, the frequencies of these cells significantly decreased with increasing CD4 T cell counts in HIV-infected patients. Although, the naïve CD4+ and CD8+ T cells were lower in HIV patients’ cohort than uninfected cohort, there was a significant increase in both naïve CD4+ and CD8+ T cells with increasing CD4 T cell counts in HIV-infected patients. The underlying mechanism behind this increased naïve CD4+ and CD8+ T cells in HIV-infected patients was due to an increase in recent thymic emigrants, CD4+CD31+, as compared to CD4+CD31-. The CD4+ T cells of HIV-infected patients produced cytokines, including IL-2, IL-10 and IFN-γ comparable to uninfected individuals. In conclusion, virologically controlled HIV-infected patients on long-term ART show a significant reduction in terminally differentiated T cells, suggestive of decreased exhaustion/senescence, and improvement in the ratios of naïve to memory and function of T cells.
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Affiliation(s)
- Nicole E Behrens
- Department of Immunobiology, College of Medicine, University of Arizona, Tucson, Arizona, United States of America
| | - Anne Wertheimer
- Department of Immunobiology, College of Medicine, University of Arizona, Tucson, Arizona, United States of America.,Department of Medicine, College of Medicine, University of Arizona, Tucson, Arizona, United States of America.,Bio5 Institute, University of Arizona, Tucson, Arizona, United States of America
| | - Stephen A Klotz
- Department of Medicine, College of Medicine, University of Arizona, Tucson, Arizona, United States of America
| | - Nafees Ahmad
- Department of Immunobiology, College of Medicine, University of Arizona, Tucson, Arizona, United States of America
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21
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Exploring the link between innate immune activation and thymic function by measuring sCD14 and TRECs in HIV patients living in Belgium. PLoS One 2017; 12:e0185761. [PMID: 29049344 PMCID: PMC5648129 DOI: 10.1371/journal.pone.0185761] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2017] [Accepted: 09/19/2017] [Indexed: 12/31/2022] Open
Abstract
Microbial translocation is now viewed as a central event in the pathogenesis of chronic inflammation during HIV infection. Thymic function failure is another crucial factor involved in HIV disease progression. The goal of this study was to explore the hypothesis of potential links between microbial translocation and thymic function in HIV-1 patients living in Belgium. The extent of microbial translocation was assessed through the measurement of soluble CD14 (sCD14). T-cell receptor excision circles (sjTRECs and dβTRECs) were used as a measure of thymic function. Data were collected from 75 HIV-infected patients. Simple and complex linear regressions were done to analyze the link between these two processes. We found a statistically relevant negative correlation between thymopoiesis (sjTREC) and sCD14 level (p = 0.004). These results suggest a link between thymic function failure, microbial translocation and innate immune activation.
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22
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Durand M, Chartrand-Lefebvre C, Baril JG, Trottier S, Trottier B, Harris M, Walmsley S, Conway B, Wong A, Routy JP, Kovacs C, MacPherson PA, Monteith KM, Mansour S, Thanassoulis G, Abrahamowicz M, Zhu Z, Tsoukas C, Ancuta P, Bernard N, Tremblay CL. The Canadian HIV and aging cohort study - determinants of increased risk of cardio-vascular diseases in HIV-infected individuals: rationale and study protocol. BMC Infect Dis 2017; 17:611. [PMID: 28893184 PMCID: PMC5594495 DOI: 10.1186/s12879-017-2692-2] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2017] [Accepted: 08/17/2017] [Indexed: 01/08/2023] Open
Abstract
Background With potent antiretroviral drugs, HIV infection is becoming a chronic disease. Emergence of comorbidities, particularly cardiovascular disease (CVD) has become a leading concern for patients living with the infection. We hypothesized that the chronic and persistent inflammation and immune activation associated with HIV disease leads to accelerated aging, characterized by CVD. This will translate into higher incidence rates of CVD in HIV infected participants, when compared to HIV negative participants, after adjustment for traditional CVD risk factors. When characterized further using cardiovascular imaging, biomarkers, immunological and genetic profiles, CVD associated with HIV will show different characteristics compared to CVD in HIV-negative individuals. Methods/design The Canadian HIV and Aging cohort is a prospective, controlled cohort study funded by the Canadian Institutes of Health Research. It will recruit patients living with HIV who are aged 40 years or older or have lived with HIV for 15 years or more. A control population, frequency matched for age, sex, and smoking status, will be recruited from the general population. Patients will attend study visits at baseline, year 1, 2, 5 and 8. At each study visit, data on complete medical and pharmaceutical history will be captured, along with anthropometric measures, a complete physical examination, routine blood tests and electrocardiogram. Consenting participants will also contribute blood samples to a research biobank. The primary outcome is incidence of a composite of: myocardial infarction, coronary revascularization, stroke, hospitalization for angina or congestive heart failure, revascularization or amputation for peripheral artery disease, or cardiovascular death. Preplanned secondary outcomes are all-cause mortality, incidence of the metabolic syndrome, incidence of type 2 diabetes, incidence of renal failure, incidence of abnormal bone mineral density and body fat distribution. Patients participating to the cohort will be eligible to be enrolled in four pre-planned sub-studies of cardiovascular imaging, glucose metabolism, immunological and genetic risk profile. Discussion The Canadian HIV and Aging Cohort will provide insights on pathophysiological pathways leading to premature CVD for patients living with HIV. Electronic supplementary material The online version of this article (10.1186/s12879-017-2692-2) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Madeleine Durand
- Internal Medicine service, Centre de Recherche du CHUM, Montréal, QC, H2J 1T8, Canada.
| | | | - Jean-Guy Baril
- Clinique médicale urbaine du Quartier latin, Montreal, Canada
| | - Sylvie Trottier
- Clinique médicale urbaine du Quartier latin, Montreal, Canada
| | - Benoit Trottier
- Clinique médicale urbaine du Quartier latin, Montreal, Canada
| | | | - Sharon Walmsley
- Division of Infectious Diseases, University Health Network, Toronto, Canada
| | - Brian Conway
- Division of Infectious Diseases, University Health Network, Toronto, Canada
| | - Alexander Wong
- Infectious Diseases Clinic, Regina Qu'Appelle Health Region, Regina, Canada
| | - Jean-Pierre Routy
- Chronic viral infection service and Division of Hematology, McGill University Health Centre, Montreal, Canada
| | - Colin Kovacs
- Maple Leaf Medical HIV Research Collaborative Inc., Toronto, Canada
| | - Paul A MacPherson
- The Ottawa Hospital Research Institute and the University of Ottawa, Ottawa, Canada
| | | | - Samer Mansour
- The Ottawa Hospital Research Institute and the University of Ottawa, Ottawa, Canada
| | - George Thanassoulis
- Preventive and Genomic Cardiology, McGill University Health Center and Research Institute, Montreal, Canada
| | - Michal Abrahamowicz
- Department of Epidemiology and Biostatistics, McGill University, Montreal, Canada
| | - Zhitong Zhu
- Department of Epidemiology and Biostatistics, McGill University, Montreal, Canada
| | - Christos Tsoukas
- McGill University, Immunology service, Montreal General Hospital, Montreal, Canada
| | | | - Nicole Bernard
- Research Institute of the McGill University Health Center, Division of Experimental Medicine, McGill University, Division of Clinical Immunology, McGill University health Center (MUHC), Chronic Viral Illness Service, Montreal, Canada
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23
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Booiman T, Wit FW, Girigorie AF, Maurer I, De Francesco D, Sabin CA, Harskamp AM, Prins M, Franceschi C, Deeks SG, Winston A, Reiss P, Kootstra NA. Terminal differentiation of T cells is strongly associated with CMV infection and increased in HIV-positive individuals on ART and lifestyle matched controls. PLoS One 2017; 12:e0183357. [PMID: 28806406 PMCID: PMC5555623 DOI: 10.1371/journal.pone.0183357] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Accepted: 08/02/2017] [Indexed: 01/26/2023] Open
Abstract
HIV-1-positive individuals on successful antiretroviral therapy (ART) are reported to have higher rates of age-associated non-communicable comorbidities (AANCCs). HIV-associated immune dysfunction has been suggested to contribute to increased AANCC risk. Here we performed a cross-sectional immune phenotype analysis of T cells in ART-treated HIV-1-positive individuals with undetectable vireamia (HIV-positives) and HIV-1-negative individuals (HIV-negatives) over 45 years of age. In addition, two control groups were studied: HIV negative adults selected based on lifestyle and demographic factors (Co-morBidity in Relation to AIDS, or COBRA) and unselected age-matched donors from a blood bank. Despite long-term ART (median of 12.2 years), HIV-infected adults had lower CD4+ T-cell counts and higher CD8+ T-cell counts compared to well-matched HIV-negative COBRA participants. The proportion of CD38+HLA-DR+ and PD-1+ CD4+ T-cells was higher in HIV-positive cohort compared to the two HIV-negative cohorts. The proportion CD57+ and CD27−CD28− cells of both CD4+ and CD8+ T-cells in HIV-positives was higher compared to unselected adults (blood bank) as reported before but this difference was not apparent in comparison with well-matched HIV-negative COBRA participants. Multiple regression analysis showed that the presence of an increased proportion of terminally differentiated T cells was strongly associated with CMV infection. Compared to appropriately selected HIV-negative controls, HIV-positive individuals on ART with long-term suppressed viraemia exhibited incomplete immune recovery and increased immune activation/exhaustion. CMV infection rather than treated HIV infection appears to have more consistent effects on measures of terminal differentiation of T cells.
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Affiliation(s)
- Thijs Booiman
- Department of Experimental Immunology, Amsterdam Infection and Immunity Institute, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
- Amsterdam Institute for Global Health and Development, Amsterdam, The Netherlands
| | - Ferdinand W. Wit
- Amsterdam Institute for Global Health and Development, Amsterdam, The Netherlands
- Department of Global Health & Division of Infectious Disease, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
- HIV Monitoring Foundation, Amsterdam, The Netherlands
| | - Arginell F. Girigorie
- Department of Experimental Immunology, Amsterdam Infection and Immunity Institute, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
- Amsterdam Institute for Global Health and Development, Amsterdam, The Netherlands
| | - Irma Maurer
- Department of Experimental Immunology, Amsterdam Infection and Immunity Institute, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Davide De Francesco
- Department of Infection and Population Health, University College London, London, United Kingdom
| | - Caroline A. Sabin
- Department of Infection and Population Health, University College London, London, United Kingdom
| | - Agnes M. Harskamp
- Department of Experimental Immunology, Amsterdam Infection and Immunity Institute, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Maria Prins
- Public health service, Amsterdam, The Netherlands
| | - Claudio Franceschi
- Department of Experimental, Diagnostic and Specialty Medicine, Alma Mater Studiorum Universita di Bologna, Bologna, Italy
| | - Steven G. Deeks
- Department of Medicine, University of California, San Francisco, California, United States of America
| | - Alan Winston
- Imperial College of Science, Technology and Medicine, London, United Kingdom
| | - Peter Reiss
- Amsterdam Institute for Global Health and Development, Amsterdam, The Netherlands
- Department of Global Health & Division of Infectious Disease, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
- HIV Monitoring Foundation, Amsterdam, The Netherlands
| | - Neeltje A. Kootstra
- Department of Experimental Immunology, Amsterdam Infection and Immunity Institute, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
- * E-mail:
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24
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Gustafson DR, Shi Q, Holman S, Minkoff H, Cohen MH, Plankey MW, Havlik R, Sharma A, Gange S, Gandhi M, Milam J, Hoover DR. Predicting death over 8 years in a prospective cohort of HIV-infected women: the Women's Interagency HIV Study. BMJ Open 2017; 7:e013993. [PMID: 28667199 PMCID: PMC5577878 DOI: 10.1136/bmjopen-2016-013993] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
OBJECTIVES Predicting mortality in middle-aged HIV-infected (HIV+) women on antiretroviral therapies (ART) is important for understanding the impact of HIV infection. Several health indices have been used to predict mortality in women with HIV infection. We evaluated: (1) an HIV biological index, Veterans Aging Cohort Study (VACS); (2) a physical index, Fried Frailty Index (FFI); and (3) a mental health index, Center for Epidemiologic Studies-Depression (CES-D). Proportional hazards regression analyses were used to predict death and included relevant covariates. DESIGN Prospective, observational cohort. SETTING Multicentre, across six sites in the USA. PARTICIPANTS 1385 multirace/ethnic ART-experienced HIV+ women in 2005. PRIMARY AND SECONDARY OUTCOMES All deaths, AIDS deaths and non-AIDS deaths up to ~8 years from baseline. RESULTS Included together in one model, VACS Index was the dominant, significant independent predictor of all deaths within 3 years (HR=2.20, 95% CI 1.83, 2.65, χ2=69.04, p<0.0001), and later than 3 years (HR=1.55, 95% CI 1.30, 1.84, χ2=23.88, p<0.0001); followed by FFI within 3 years (HR=2.06, 95% CI 1.19, 3.57, χ2=6.73, p=0.01) and later than 3 years (HR=2.43, 95% CI 1.58, 3.75, χ2=16.18, p=0.0001). CES-D score was not independently associated with mortality. CONCLUSIONS AND RELEVANCE This is the first simultaneous evaluation of three common health indices in HIV+ adults. Indices reflecting physical and biological ageing were associated with death.
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Affiliation(s)
- Deborah R Gustafson
- Department of Neurology, State University of New York-Downstate Medical Center, Brooklyn, New York, USA
| | - Qiuhu Shi
- School of Health Sciences and Practice, New York Medical College, Valhalla, New York, USA
| | - Susan Holman
- Department of Medicine, State University of New York-Downstate Medical Center, Brooklyn, New York, USA
| | - Howard Minkoff
- Maimonides Medical Center, Brooklyn, New York, USA
- Department of Obstetrics and Gynecology, State University of New York-Downstate Medical Center, Brooklyn, New York, USA
| | - Mardge H Cohen
- Department of Medicine, Stroger Hospital of Cook County Health and Hospital System and Rush University, Chicago, Illinois, USA
| | - Michael W Plankey
- Department of Medicine, Division of Infectious Diseases, Georgetown University Medical Center, Washington, DC, USA
| | - Richard Havlik
- AIDS Community Research Initiative of America, New York, New York, USA
- Arrow Health, Bethesda, Maryland, USA
| | - Anjali Sharma
- Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA
| | - Stephen Gange
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
| | - Monica Gandhi
- Department of Medicine, University of California, San Francisco, California, USA
| | - Joel Milam
- Department of Preventive Medicine, University of Southern California, Los Angeles, California, USA
| | - Donald R Hoover
- Department of Statistics and Biostatistics and Institute for Health, Health Care Policy and Aging Research, Rutgers the State University of New Jersey, New Brunswick, New Jersey, USA
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Dock J, Hultin L, Hultin P, Elliot J, Yang OO, Anton PA, Jamieson BD, Effros RB. Human immune compartment comparisons: Optimization of proliferative assays for blood and gut T lymphocytes. J Immunol Methods 2017; 445:77-87. [PMID: 28336395 PMCID: PMC5505254 DOI: 10.1016/j.jim.2017.03.014] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2016] [Revised: 01/30/2017] [Accepted: 03/17/2017] [Indexed: 11/20/2022]
Abstract
The accumulation of peripheral blood late-differentiated memory CD8 T cells with features of replicative (cellular) senescence, including inability to proliferate in vitro, has been extensively studied. Importantly, the abundance of these cells is directly correlated with increased morbidity and mortality in older persons. Of note, peripheral blood contains only 2% of the total body lymphocyte population. By contrast, the gut-associated lymphoid tissue (GALT) is the most extensive lymphoid organ, housing up to 60% of total body lymphocytes, but has never been assessed with respect to senescence profiles. We report here the development of a method for measuring and comparing proliferative capacity of peripheral blood and gut colorectal mucosa-derived CD8 T cells. The protocol involves a 5-day culture of mononuclear leukocyte populations, from blood and gut colorectal mucosa respectively, labeled with 5-(and 6)-carboxyfluorescein diacetate succinimidyl ester (CFSE) and 5-bromo-2'-deoxyuridine (BrdU) and stimulated with anti-CD2/3/28-linked microbeads. Variables tested and optimized as part of the protocol development include: mode of T cell stimulation, CFSE concentration, inclusion of a second proliferation marker, BrdU, culture duration, initial culture concentration, and inclusion of autologous irradiated feeder cells. Moving forward, this protocol demonstrates a significant advance in the ability of researchers to study compartment-specific differences of in vitro proliferative dynamics of CD8 T cells, as an indicator of replicative senescence and immunological aging. The study's two main novel contributions are (1) Optimization and adaptation of standard proliferative dynamics blood T cell protocols for T cells within the mucosal immune system. (2) Introduction of the novel technique of combining CFSE and BrdU staining to do so.
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Affiliation(s)
- Jeffrey Dock
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA 90095, United States
| | - Lance Hultin
- Division of Hematology and Oncology, Department of Medicine, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA 90095, United States; UCLA AIDS Institute, David Geffen School of Medicine at UCLA, United States
| | - Patricia Hultin
- Department of Epidemiology, Fielding School of Public Health, University of California-Los Angeles, Los Angeles, CA 90095, United States; UCLA AIDS Institute, David Geffen School of Medicine at UCLA, United States
| | - Julie Elliot
- Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA 90095, United States; UCLA AIDS Institute, David Geffen School of Medicine at UCLA, United States
| | - Otto O Yang
- Division of Infectious Diseases, Department of Medicine, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA 90095, United States; Department of Microbiology Immunology & Molecular Genetics, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA 90095, United States; UCLA AIDS Institute, David Geffen School of Medicine at UCLA, United States; AIDS Healthcare Foundation, Los Angeles, CA 90028, United States
| | - Peter A Anton
- Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA 90095, United States; UCLA AIDS Institute, David Geffen School of Medicine at UCLA, United States
| | - Beth D Jamieson
- Division of Hematology and Oncology, Department of Medicine, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA 90095, United States; UCLA AIDS Institute, David Geffen School of Medicine at UCLA, United States
| | - Rita B Effros
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA 90095, United States; UCLA AIDS Institute, David Geffen School of Medicine at UCLA, United States.
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Accelerated disease progression and robust innate host response in aged SIVmac239-infected Chinese rhesus macaques is associated with enhanced immunosenescence. Sci Rep 2017; 7:37. [PMID: 28232735 PMCID: PMC5428349 DOI: 10.1038/s41598-017-00084-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2016] [Accepted: 01/31/2017] [Indexed: 02/06/2023] Open
Abstract
The elderly population infected with HIV-1 is often characterized by the rapid AIDS progression and poor treatment outcome, possibly because of immunosenescence resulting from both HIV infection and aging. However, this hypothesis remains to be fully tested. Here, we studied 6 young and 12 old Chinese rhesus macaques (ChRM) over the course of three months after simian immunodeficiency virus (SIV) SIVmac239 infection. Old ChRM showed a higher risk of accelerated AIDS development than did young macaques, owing to rapidly elevated plasma viral loads and decreased levels of CD4+ T cells. The low frequency of naïve CD4+ T cells before infection was strongly predictive of an increased disease progression, whereas the severe depletion of CD4+ T cells and the rapid proliferation of naïve lymphocytes accelerated the exhaustion of naïve lymphocytes in old ChRM. Moreover, in old ChRM, a robust innate host response with defective regulation was associated with a compensation for naïve T cell depletion and a high level of immune activation. Therefore, we suggest that immunosenescence plays an important role in the accelerated AIDS progression in elderly individuals and that SIV-infected old ChRM may be a favorable model for studying AIDS pathogenesis and researching therapies for elderly AIDS patients.
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Agwu AL, Fleishman JA, Mahiane G, Nonyane BAS, Althoff KN, Yehia BR, Berry SA, Rutstein R, Nijhawan A, Mathews C, Aberg JA, Keruly JC, Moore RD, Gebo KA. Comparing longitudinal CD4 responses to cART among non-perinatally HIV-infected youth versus adults: Results from the HIVRN Cohort. PLoS One 2017; 12:e0171125. [PMID: 28182675 PMCID: PMC5300758 DOI: 10.1371/journal.pone.0171125] [Citation(s) in RCA: 2] [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: 09/20/2016] [Accepted: 01/15/2017] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Youth have residual thymic tissue and potentially greater capacity for immune reconstitution than adults after initiation of combination antiretroviral therapy (cART). However, youth face behavioral and psychosocial challenges that may make them more likely than adults to delay ART initiation and less likely to attain similar CD4 outcomes after initiating cART. This study compared CD4 outcomes over time following cART initiation between ART-naïve non-perinatally HIV-infected (nPHIV) youth (13-24 years-old) and adults (≥25-44 years-old). METHODS Retrospective analysis of ART-naïve nPHIV individuals 13-44 years-old, who initiated their first cART between 2008 and 2011 at clinical sites in the HIV Research Network. A linear mixed model was used to assess the association between CD4 levels after cART initiation and age (13-24, 25-34, 35-44 years), accounting for random variation within participants and between sites, and adjusting for key variables including gender, race/ethnicity, viral load, gaps in care (defined as > 365 days between CD4 tests), and CD4 levels prior to cART initiation (baseline CD4). RESULTS Among 2,595 individuals (435 youth; 2,160 adults), the median follow-up after cART initiation was 179 weeks (IQR 92-249). Baseline CD4 was higher for youth (320 cells/mm3) than for ages 25-34 (293) or 35-44 (258). At 239 weeks after cART initiation, median unadjusted CD4 was higher for youth than adults (576 vs. 539 and 476 cells/mm3, respectively), but this difference was not significant when baseline CD4 was controlled. Compared to those with baseline CD4 ≤200 cells/mm3, individuals with baseline CD4 of 201-500 and >500 cells/mm3 had greater predicted CD4 levels: 390, 607, and 831, respectively. Additionally, having no gaps in care and higher viral load were associated with better CD4 outcomes. CONCLUSIONS Despite having residual thymic tissue, youth attain similar, not superior, CD4 gains as adults. Early ART initiation with minimal delay is as essential to optimizing outcomes for youth as it is for their adult counterparts.
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Affiliation(s)
- Allison L. Agwu
- Division of Pediatric Infectious Diseases, Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore, MD, United States of America
- Division of Infectious Diseases, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, United States of America
| | - John A. Fleishman
- Center for Financing, Access, and Cost Trends, Agency for Healthcare Research and Quality, Rockville, MD, United States of America
| | - Guy Mahiane
- Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States of America
| | - Bareng Aletta Sanny Nonyane
- Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States of America
| | - Keri N. Althoff
- Bloomberg School of Public Health, Johns Hopkins Medical Institutions, Baltimore, MD, United States of America
| | - Baligh R. Yehia
- Division of Infectious Diseases, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, United States of America
| | - Stephen A. Berry
- Division of Infectious Diseases, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, United States of America
| | - Richard Rutstein
- Division of General Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA, United States of America
| | - Ank Nijhawan
- Department of Internal Medicine, UT Southwestern Medical Center, Parkland Health and Hospital System, Dallas TX, United States of America
| | - Christopher Mathews
- Department of Medicine, University of California San Diego, San Diego, CA, United States of America
| | - Judith A. Aberg
- Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
| | - Jeanne C. Keruly
- Division of Infectious Diseases, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, United States of America
| | - Richard D. Moore
- Division of General Internal Medicine, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, United States of America
| | - Kelly A. Gebo
- Division of Infectious Diseases, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, United States of America
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Abstract
PURPOSE OF THE REVIEW The number of adults who are aging successfully and have HIV infection is increasing. More effective antiretroviral therapy (ART) regimens are preventing individuals infected with HIV from reaching end stages of the HIV infection and developing AIDS (acquired immunodeficiency syndrome). However, even at lower viral loads, chronic HIV infection appears to have consequences on aging processes, including the development of frailty. RECENT FINDINGS Frailty is a term used to describe vulnerability in aging. Frailty indices such as the Fried Frailty Index (FFI), the Veterans Aging Cohort Study (VACS) Index, and the Center for Epidemiologic Studies Depression scale (CES-D), an index of emotional frailty, associate with or predict clinical outcomes and death. However, even among existing frailty definitions, components require rigorous and consistent standardization. In the Women's Interagency HIV Study (WIHS), we have shown that frailty does not exist in isolation, even in midlife, and we use frailty to predict death. Frailty indices should be systematically used by health professionals to evaluate health and future risks for adverse events. Frailty prevention efforts, especially among those with HIV infection, appear to be essential for "successful aging" or aging without disability or loss of independence and may prevent HIV transmission. Taking care of elderly people is one of the major challenges of this century, and we must expect and be prepared for an increase in the number of aging adults, some of whom are patients with many co-morbidities and HIV infection.
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Affiliation(s)
- Marion Thurn
- Department of Neurology, State University of New York Downstate Medical Center, 450 Clarkson Avenue, Box 1213, Brooklyn, NY, 11203, USA
| | - Deborah R Gustafson
- Department of Neurology, State University of New York Downstate Medical Center, 450 Clarkson Avenue, Box 1213, Brooklyn, NY, 11203, USA.
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Jourjy J, Dahl K, Huesgen E. Antiretroviral Treatment Efficacy and Safety in Older HIV-Infected Adults. Pharmacotherapy 2016; 35:1140-51. [PMID: 26684554 DOI: 10.1002/phar.1670] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Highly active antiretroviral therapy (ART) and its widespread availability have revolutionized the landscape of HIV care and patient outcomes, transforming infection with HIV into a manageable chronic condition rather than a life-limiting disease. This transformation has created an older patient demographic. The effect that older age has on the outcomes of ART is not completely understood. Limited data are available in older individuals due to underrepresentation in clinical trials. To better understand this relationship, we conducted a literature search to assess the impact of older age on the outcomes of ART in the older HIV-infected population, including immunologic and virologic outcomes, mortality, disease progression, toxicity of ART, and pharmacokinetic considerations. In addition, package inserts of antiretroviral (ARV) medications were reviewed for efficacy, safety, and pharmacokinetic information pertaining to the older population. Most studies in older adults (50 yrs or older) demonstrated slower and blunted CD4 immune recovery but better virologic suppression in response to ART. Higher rates of mortality and faster disease progression have been observed in adults 50 years and older, particularly during the first year after ART initiation. HIV-infected patients aged 50 years and older appear to be at greater risk for certain ART-associated toxicities including nephrotoxicity, decline in bone mineral density and bone fracture, symptomatic peripheral neuropathy, and cardiovascular disease including myocardial infarction. The available literature suggests that clinicians should consider avoiding agents such as tenofovir disoproxil fumarate (TDF) in older patients with risk factors for renal impairment and/or osteoporosis. If TDF is used in patients aged 50 years or older, more frequent monitoring should be considered. Older age was a significant predictor for higher atazanavir exposure and higher lopinavir trough concentration at 24 weeks. The clinical implications of these findings are unknown. It is imperative that future development of novel ARV drug therapies includes a greater proportion of older subjects in clinical trials.
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Affiliation(s)
- Jacqueline Jourjy
- Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, Florida
| | - Keelin Dahl
- Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, Florida
| | - Emily Huesgen
- Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, Florida
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HIV Infection in the Elderly: Arising Challenges. J Aging Res 2016; 2016:2404857. [PMID: 27595022 PMCID: PMC4993911 DOI: 10.1155/2016/2404857] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2016] [Revised: 06/14/2016] [Accepted: 06/30/2016] [Indexed: 12/27/2022] Open
Abstract
Globally there is an increase in the number of people living with HIV at an advanced age (50 years and above). This is mainly due to prolonged survival following the use of highly active antiretroviral therapy. Living with HIV at an advanced age has been shown to be associated with a number of challenges, both clinical and immunological. This minireview aims at discussing the challenges encountered by elderly HIV-infected patients.
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Gustafson DR, Shi Q, Thurn M, Holman S, Minkoff H, Cohen M, Plankey MW, Havlik R, Sharma A, Gange S, Gandhi M, Milam J, Hoover D. Frailty and Constellations of Factors in Aging HIV-infected and Uninfected Women--The Women's Interagency HIV Study. J Frailty Aging 2016; 5:43-8. [PMID: 26980368 DOI: 10.14283/jfa.2016.79] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
BACKGROUND Biological similarities are noted between aging and HIV infection. Middle-aged adults with HIV infection may present as elderly due to accelerated aging or having more severe aging phenotypes occurring at younger ages. OBJECTIVES We explored age-adjusted prevalence of frailty, a geriatric condition, among HIV+ and at risk HIV- women. DESIGN Cross-sectional. SETTING The Women's Interagency HIV Study (WIHS). PARTICIPANTS 2028 middle-aged (average age 39 years) female participants (1449 HIV+; 579 HIV-). MEASUREMENTS The Fried Frailty Index (FFI), HIV status variables, and constellations of variables representing Demographic/health behaviors and Aging-related chronic diseases. Associations between the FFI and other variables were estimated, followed by stepwise regression models. RESULTS Overall frailty prevalence was 15.2% (HIV+, 17%; HIV-, 10%). A multivariable model suggested that HIV infection with CD4 count<200; age>40 years; current or former smoking; income ≤$12,000; moderate vs low fibrinogen-4 (FIB-4) levels; and moderate vs high estimated glomerular filtration rate (eGFR) were positively associated with frailty. Low or moderate drinking was protective. CONCLUSIONS Frailty is a multidimensional aging phenotype observed in mid-life among women with HIV infection. Prevalence of frailty in this sample of HIV-infected women exceeds that for usual elderly populations. This highlights the need for geriatricians and gerontologists to interact with younger 'at risk' populations, and assists in the formulation of best recommendations for frailty interventions to prevent early aging, excess morbidities and early death.
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Affiliation(s)
- D R Gustafson
- Deborah Gustafson, PhD, MS, Professor, Department of Neurology, SUNY Downstate Medical Center, 450 Clarkson Ave, MSC 1213, Brooklyn, NY 11203, United States, , Phone: +1-718-270-1581, Fax: 718-221-5761
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CD4+/CD8+ ratio, age, and risk of serious noncommunicable diseases in HIV-infected adults on antiretroviral therapy. AIDS 2016; 30:899-908. [PMID: 26959354 DOI: 10.1097/qad.0000000000001005] [Citation(s) in RCA: 89] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
OBJECTIVE In virologically suppressed HIV-infected adults, noncommunicable diseases (NCDs) have been associated with immune senescence and low CD4/CD8 lymphocyte ratio. Age differences in the relationship between CD4/CD8 ratio and NCDs have not been described. DESIGN Observational cohort study. METHODS We assessed CD4/CD8 ratio and incident NCDs (cardiovascular, cancer, liver, and renal diseases) in HIV-infected adults started on antiretroviral therapy between 1998 and 2012. Study inclusion began once patients maintained virologic suppression for 12 months (defined as baseline). We examined age and baseline CD4/CD8 ratio and used Cox proportional hazard models to assess baseline CD4/CD8 ratio and NCDs. RESULTS This study included 2006 patients. Low baseline CD4/CD8 ratio was associated with older age, male sex, and low CD4 lymphocyte counts. In models adjusting for CD4 lymphocyte count, CD4/CD8 ratio was inversely associated with age (P < 0.01). Among all patients, 182 had incident NCDs, including 46 with coronary artery disease (CAD) events. CD4/CD8 ratio was inversely associated with risk of CAD events [adjusted HR per 0.1 increase in CD4/CD8 ratio = 0.87, 95% confidence interval (CI): 0.76-0.99, P = 0.03]. This association was driven by those under age 50 years (adjusted HR 0.83 [0.70-0.97], P = 0.02) vs. those over age 50 years (adjusted HR = 0.96 [0.79-1.18], P = 0.71). CD4/CD8 ratio was not significantly associated with incident noncardiac NCDs. CONCLUSIONS Higher CD4/CD8 ratio after 1 year of HIV virologic suppression was independently predictive of decreased CAD risk, particularly among younger adults. Advanced immune senescence may contribute to CAD events in younger HIV patients on antiretroviral therapy.
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Immunological and Clinical Responses following the Use of Antiretroviral Therapy among Elderly HIV-Infected Individuals Attending Care and Treatment Clinic in Northwestern Tanzania: A Retrospective Cohort Study. JOURNAL OF SEXUALLY TRANSMITTED DISEASES 2016; 2016:5235269. [PMID: 27042375 PMCID: PMC4794567 DOI: 10.1155/2016/5235269] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 10/05/2015] [Revised: 02/09/2016] [Accepted: 02/14/2016] [Indexed: 11/26/2022]
Abstract
Background. Limited information exists on adults ≥50 years receiving HIV care in sub-Saharan Africa despite their increasing number. We aimed at studying immunologic and clinical responses to ART in this population. Methods. Data of patients who initiated HAART between 30th of June 2004 and 1st of May 2008 at Sekou Toure Care and Treatment Clinic were retrospectively analyzed. Date of ART initiation was used as a baseline and 48 months as a follow-up date. Immune recovery was defined as a CD4 count of ≥350 cells/mm3 at 48 months and late presentation as presentation with WHO stage 3 or 4 at clinic enrollment. Proportions of patients reaching this endpoint were compared between the two groups. Results. A total of 728 patients were included in our study; of these 73 (10.0%) were aged 50 years and above. Late presentation was more common in elderly patients than young patients (65.7% versus 56.1%, P = 0.12). Proportion of patients with CD4 count ≥350 (immune recovery) was higher in younger patients than in elderly patients, although this was not statistically significant (54.5% versus 44.9%, P = 0.2). Median absolute increase in CD4 at 48 months was higher in younger patients than in elderly patients (+241.5 cells/mm3 versus +146 cells/mm3, P = 0.007). Conclusion. Elderly HIV patients have higher rates of late presentation, with lower immune recovery. Strategies to increase HIV testing in this group are required for early diagnosis and treatment to improve outcomes.
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Elevation and persistence of CD8 T-cells in HIV infection: the Achilles heel in the ART era. J Int AIDS Soc 2016; 19:20697. [PMID: 26945343 PMCID: PMC4779330 DOI: 10.7448/ias.19.1.20697] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2015] [Revised: 01/15/2016] [Accepted: 01/28/2016] [Indexed: 12/18/2022] Open
Abstract
Introduction HIV infection leads to a disturbed T-cell homeostasis, featured by a depletion of CD4 T-cells and a persistent elevation of CD8 T-cells over disease progression. Most effort of managing HIV infection has been focused on CD4 T-cell recovery, while changes in the CD8 compartment were relatively underappreciated in the past. Methods A comprehensive literature review of publications in English language was conducted using major electronic databases. Our search was focused on factors contributing to CD8 T-cell dynamics in HIV infection and following antiretroviral therapy (ART). Discussion Normalization of CD8 counts is seldom observed even with optimal CD4 recovery following long-term treatment. Initiation of ART in primary HIV infection leads to enhanced normalization of CD8 count compared with long-term ART initiated in chronic infection. Importantly, such CD8 elevation in treated HIV infection is associated with an increased risk of inflammatory non-AIDS-related clinical events independent of CD4 T-cell recovery. The mechanisms underlying CD8 persistence remain largely unknown, which may include bystander activation, exhaustion and immunosenescence of CD8 T-cells. The information provided herein will lead to a better understanding of factors associated with CD8 persistence and contribute to the development of strategies aiming at CD8 normalization. Conclusions Persistence of CD8 T-cell elevation in treated HIV-infected patients is associated with an increased risk of non-AIDS-related events. Now that advances in ART have led to decreased AIDS-related opportunistic diseases, more attention has been focused on reducing non-AIDS events and normalizing persistent CD8 T-cell elevation.
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Kowalska JD, Kubicka J, Siwak E, Pulik P, Firląg-Burkacka E, Horban A. Factors associated with the first antiretroviral therapy modification in older HIV-1 positive patients. AIDS Res Ther 2016; 13:2. [PMID: 26744599 PMCID: PMC4704295 DOI: 10.1186/s12981-015-0084-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2014] [Accepted: 11/30/2015] [Indexed: 01/09/2023] Open
Abstract
Background Rates of first antiretroviral therapy (cART) modifications are high in most observational studies. The age-related differences in treatment duration and characteristics of first cART modifications remain underinvestigated. With increasing proportion of older patients in HIV population it is important to better understand age-related treatment effects. Methods Patients were included into this analysis, if being cART naïve at the first visit at the clinic. Follow-up time was measured from the first visit date until first cART modification or 28 February 2013. First cART modification was defined as any change in the third drug component i.e. protease inhibitor (PI), non-nucleoside reverse transcriptase inhibitor (NNRTI), integrase inhibitor or fusion inhibitor. Cox proportional hazard models were used to identify factors related to first cART modification in three age groups: <30, 30–50 and >50. Results In total 2027 patients with 14,965 person-years of follow-up (PYFU) were included. The oldest group included 136 patients with 1901, middle group 1202 with 8416 PYFU and youngest group consisted of 689 patients with 4648 PYFU. Median follow-up time was 5.8 (IQR 3.4–9.4) years, median time on first cART was 4.4 (IQR 2.1–8.5) years. 72.4 % of patients started PI-based and 26.1 % NNRTI-based regimen. In total 1268 (62.5 %) patients had cART modification (non-adherence 30.8 %, toxicity 29.6 %). Durability of first cART was the best in patients over 50 y.o. (log-rank test, p = 0.001). Factors associated with discontinuation in this group were late presentation (HR 0.45, [95 % CI 0.23–0.90], p = 0.02) and PI use (HR 2.17, [95 % CI 1.18–4.0], p = 0.01). Conclusions Rates of first cART modifications or discontinuation were comparable in all groups; however older patients were significantly longer on first cART regimen.
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De Pablo-Bernal RS, Ramos R, Genebat M, Cañizares J, Rafii-El-Idrissi Benhnia M, Muñoz-Fernández MA, Pacheco YM, Galvá MI, Leal M, Ruiz-Mateos E. Phenotype and Polyfunctional Deregulation Involving Interleukin 6 (IL-6)- and IL-10-Producing Monocytes in HIV-Infected Patients Receiving Combination Antiretroviral Therapy Differ From Those in Healthy Older Individuals. J Infect Dis 2015; 213:999-1007. [PMID: 26518043 DOI: 10.1093/infdis/jiv520] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2015] [Accepted: 10/08/2015] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Despite the relevance of monocytes as promoters of the inflammatory response, whether human immunodeficiency virus (HIV) infection induces premature age-related changes to the phenotype and function of monocytes or whether these alterations are different and/or specifically driven by HIV remains to be mechanistically determined. METHODS We assayed the activation phenotype and the responsiveness in vitro to Toll-like receptor (TLR) agonists in classical, intermediate, and nonclassical subsets of monocytes by assessing intracellular interleukin 1α (IL-1α), IL-1β, interleukin 6 (IL-6), interleukin 8, tumor necrosis factor α, and interleukin 10 (IL-10) production in 20 HIV-infected patients receiving combination antiretroviral therapy (cART) and 2 groups of uninfected controls (20 age-matched young individuals and 20 older individuals aged >65 years). RESULTS HIV-infected patients showed a more activated phenotype of monocytes than older controls. Regarding functionality, under unstimulated conditions HIV-infected patients showed a higher percentage of classical monocytes producing IL-6 and IL-10 than control subjects. The percentage of cells with production of multiple cytokines (polyfunctionality), including IL-10, in response to TLR agonists was greater among HIV-infected patients than among control subjects. CONCLUSIONS Inflammatory alterations associated with monocytes during HIV infection are different from those in aging individuals. This monocyte dysfunction, mainly characterized by high levels of IL-6- and IL-10-producing monocytes, may have clinical implications in HIV-infected patients that are different from those in aging individuals.
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Affiliation(s)
- R S De Pablo-Bernal
- Laboratory of Immunovirology, Clinical Unit of Infectious Diseases, Microbiology, and Preventive Medicine, Institute of Biomedicine of Seville, Virgen del Rocío University Hospital/CSIC/University of Seville
| | | | - M Genebat
- Laboratory of Immunovirology, Clinical Unit of Infectious Diseases, Microbiology, and Preventive Medicine, Institute of Biomedicine of Seville, Virgen del Rocío University Hospital/CSIC/University of Seville
| | | | - M Rafii-El-Idrissi Benhnia
- Laboratory of Immunovirology, Clinical Unit of Infectious Diseases, Microbiology, and Preventive Medicine, Institute of Biomedicine of Seville, Virgen del Rocío University Hospital/CSIC/University of Seville Department of Medical Biochemistry and Molecular Biology and Immunology, Medical School, University of Seville
| | - M A Muñoz-Fernández
- Laboratory of Molecular Immunobiology, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón Networking Research Center on Bioengineering, Biomaterials, and Nanomedicine, Madrid, Spain
| | - Y M Pacheco
- Laboratory of Immunovirology, Clinical Unit of Infectious Diseases, Microbiology, and Preventive Medicine, Institute of Biomedicine of Seville, Virgen del Rocío University Hospital/CSIC/University of Seville
| | | | - M Leal
- Laboratory of Immunovirology, Clinical Unit of Infectious Diseases, Microbiology, and Preventive Medicine, Institute of Biomedicine of Seville, Virgen del Rocío University Hospital/CSIC/University of Seville
| | - E Ruiz-Mateos
- Laboratory of Immunovirology, Clinical Unit of Infectious Diseases, Microbiology, and Preventive Medicine, Institute of Biomedicine of Seville, Virgen del Rocío University Hospital/CSIC/University of Seville
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Gustafson DR, Mielke MM, Keating SA, Holman S, Minkoff H, Crystal HA. Leptin, Adiponectin and Cognition in Middle-aged HIV-infected and Uninfected Women. The Brooklyn Women's Interagency HIV Study. JOURNAL OF GERONTOLOGY & GERIATRIC RESEARCH 2015; 4:240. [PMID: 27536467 PMCID: PMC4984413 DOI: 10.4172/2167-7182.1000240] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
CONTEXT Case-control study of women with and without HIV infection. OBJECTIVE To explore the association of cognition and the adipokines, leptin and adiponectin (total; high molecular weight, HMW), in women with (HIV+) and without HIV (HIV-) infection. DESIGN Cross-sectional analyses of adipokines and cognition using linear regression models of log-transformed adipokines, and Trails A, Trails B, Stroop interference time, Stroop word recall, Stroop color naming and reading, and Symbol Digit Modalities Test (SDMT) with consideration for age, HIV infection status, education, CD4 count, diabetes, body mass index (BMI), waist circumference (WC) and race/ethnicity. SETTING Brooklyn, NY. PARTICIPANTS 354 participants (247 HIV+, 107 HIV-), in the Brooklyn Women's Interagency HIV Study (WIHS), average age 38.9 years, with measured levels of leptin and adiponectin (total and high molecular weight, HMW). MAIN OUTCOME MEASURE Cognition. RESULTS Higher levels of leptin were positively associated with worse cognition on the basis of Trails A completion time and SDMT score. Among at risk HIV- women, leptin was associated with worse performance on Trails B. No associations were observed for total or HMW adiponectin. CONCLUSION Blood adipokine levels were measured to provide mechanistic insights regarding the association of adipose with cognitive function. These data suggest that higher levels of leptin, consistent with more adipose tissue, are associated with worse cognitive function in middle age. Monitoring leptin over time and with increasing age in relation to cognition and dementia, may lend insights to the role of adipose tissue in successful body and brain aging among women with HIV infection.
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Affiliation(s)
- Deborah R Gustafson
- Department of Neurology, State University of New York, Downstate Medical Center, Brooklyn, NY, USA
- Neuropsychiatric Epidemiology Unit, University of Gothenburg, Gothenburg, Sweden
| | - Michelle M Mielke
- Department of Health Sciences Research, Division of Epidemiology, and Department of Neurology, Mayo Clinic, Rochester, MN, USA
| | | | - Susan Holman
- Department of Medicine/STAR Clinic, State University of New York, Downstate Medical Center Maimonides Medical Center, Brooklyn, USA
| | - Howard Minkoff
- Department of Obstetrics and Gynecology, State University of New York, Downstate Medical Center, Brooklyn, USA
| | - Howard A Crystal
- Department of Neurology, State University of New York, Downstate Medical Center, Brooklyn, NY, USA
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Poor functional immune recovery in aged HIV-1-infected patients following successfully treatment with antiretroviral therapy. Hum Immunol 2015; 76:701-10. [PMID: 26429325 DOI: 10.1016/j.humimm.2015.09.023] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2015] [Revised: 04/21/2015] [Accepted: 09/27/2015] [Indexed: 01/09/2023]
Abstract
Aging is now a well-recognized characteristic of the HIV-infected population and both AIDS and aging are characterized by a deficiency of the T-cell compartment. The objective of the present study was to evaluate the impact of antiretroviral (ARV) therapy in recovering functional response of T cells to both HIV-1-specific ENV peptides (ENV) and tetanus toxoid (TT), in young and aged AIDS patients who responded to ARV therapy by controlling virus replication and elevating CD4(+) T cell counts. Here, we observed that proliferative response of T-cells to either HIV-1-specific Env peptides or tetanus toxoid (TT) was significantly lower in older antiretroviral (ARV)-treated patients. With regard to cytokine profile, lower levels of IFN-γ, IL-17 and IL-21, associated with elevated IL-10 release, were produced by Env- or TT-stimulated T-cells from older patients. The IL-10 neutralization by anti-IL-10 mAb did not elevate IFN-γ and IL-21 release in older patients. Finally, even after a booster dose of TT, reduced anti-TT IgG titers were quantified in older AIDS patients and it was related to both lower IL-21 and IFN-γ production and reduced frequency of central memory T-cells. Our results reveal that ARV therapy, despite the adequate recovery of CD4(+) T cell counts and suppression of viremia, was less efficient in recovering adequate immune response in older AIDS patients.
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Echeverría A, Moro-García MA, Asensi V, Cartón JA, López-Larrea C, Alonso-Arias R. CD4⁺CD28null T lymphocytes resemble CD8⁺CD28null T lymphocytes in their responses to IL-15 and IL-21 in HIV-infected patients. J Leukoc Biol 2015; 98:373-84. [PMID: 26034206 DOI: 10.1189/jlb.1a0514-276rr] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2014] [Accepted: 05/01/2015] [Indexed: 01/09/2023] Open
Abstract
HIV-infected individuals suffer from accelerated immunologic aging. One of the most prominent changes during T lymphocyte aging is the accumulation of CD28(null) T lymphocytes, mainly CD8(+) but also CD4(+) T lymphocytes. Enhancing the functional properties of these cells may be important because they provide antigen-specific defense against chronic infections. The objective of this study was to compare the responses of CD4(+)CD28(null) and CD8(+)CD28(null) T lymphocytes from HIV-infected patients to the immunomodulatory effects of cytokines IL-15 and IL-21. We quantified the frequencies of CD4(+)CD28(null) and CD8(+)CD28(null) T lymphocytes in peripheral blood from 110 consecutive, HIV-infected patients and 25 healthy controls. Patients showed increased frequencies of CD4(+)CD28(null) and CD8(+)CD28(null). Both subsets were positively correlated to each other and showed an inverse correlation with the absolute counts of CD4(+) T lymphocytes. Higher frequencies of HIV-specific and CMV-specific cells were found in CD28(null) than in CD28(+) T lymphocytes. Activation of STAT5 by IL-15 and STAT3 by IL-21 was higher in CD28(null) compared with CD28(+) T lymphocytes. Proliferation, expression of CD69, and IFN-γ production in CD28(null) T lymphocytes were increased after treatment with IL-15, and IL-21 potentiated most of those effects. Nevertheless, IL-21 alone reduced IFN-γ production in response to anti-CD3 stimulation but increased CD28 expression, even counteracting the inhibitory effect of IL-15. Intracytoplasmic stores of granzyme B and perforin were increased by IL-15, whereas IL-21 and simultaneous treatment with the 2 cytokines also significantly enhanced degranulation in CD4(+)CD28(null) and CD8(+)CD28(null) T lymphocytes. IL-15 and IL-21 could have a role in enhancing the effector response of CD28(null) T lymphocytes against their specific chronic antigens in HIV-infected patients.
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Affiliation(s)
- Ainara Echeverría
- *Immunology Department and Infectious Diseases Unit, Hospital Universitario Central de Asturias, Oviedo, Spain; and Fundación Renal "Iñigo Alvarez de Toledo," Madrid, Spain
| | - Marco A Moro-García
- *Immunology Department and Infectious Diseases Unit, Hospital Universitario Central de Asturias, Oviedo, Spain; and Fundación Renal "Iñigo Alvarez de Toledo," Madrid, Spain
| | - Víctor Asensi
- *Immunology Department and Infectious Diseases Unit, Hospital Universitario Central de Asturias, Oviedo, Spain; and Fundación Renal "Iñigo Alvarez de Toledo," Madrid, Spain
| | - José A Cartón
- *Immunology Department and Infectious Diseases Unit, Hospital Universitario Central de Asturias, Oviedo, Spain; and Fundación Renal "Iñigo Alvarez de Toledo," Madrid, Spain
| | - Carlos López-Larrea
- *Immunology Department and Infectious Diseases Unit, Hospital Universitario Central de Asturias, Oviedo, Spain; and Fundación Renal "Iñigo Alvarez de Toledo," Madrid, Spain
| | - Rebeca Alonso-Arias
- *Immunology Department and Infectious Diseases Unit, Hospital Universitario Central de Asturias, Oviedo, Spain; and Fundación Renal "Iñigo Alvarez de Toledo," Madrid, Spain
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Zheng L, Taiwo B, Gandhi RT, Hunt PW, Collier AC, Flexner C, Bosch RJ. Factors associated with CD8+ T-cell activation in HIV-1-infected patients on long-term antiretroviral therapy. J Acquir Immune Defic Syndr 2015; 67:153-60. [PMID: 25072610 DOI: 10.1097/qai.0000000000000286] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
BACKGROUND Abnormal levels of CD8 T-cell activation persist in HIV-1-infected patients on suppressive antiretroviral therapy (ART) and may be deleterious. METHODS CD8 T-cell activation (% coexpressing CD38/HLA-DR) was analyzed on blood specimens from 833 HIV-1-infected patients on ART for ≥96 weeks with concurrent plasma HIV RNA (vRNA) ≤200 copies per milliliter. Factors associated with CD8 T-cell activation were assessed using generalized estimating equations to incorporate longitudinal measurements (median 4/participant). RESULTS Participants were 84% men, 47% white, 28% black, and 22% Hispanic, with median pre-ART age 38 years and median ART exposure 144 weeks. CD8 T-cell activation was higher at timepoints when vRNA was 51-200 versus ≤50 copies per milliliter [mean CD8 T-cell activation 23.4% vs. 19.7%; adjusted difference: 1.7% (95% confidence interval: 0.1 to 3.4), P = 0.042]. Restricting to vRNA ≤50 copies per milliliter, multivariable models showed the following factors associated with higher CD8 T-cell activation: older age [≥45 vs. ≤30 years: 3.6% (1.4 to 5.7), P = 0.004], hepatitis C virus antibody positivity [3.6% (0.9 to 6.2), P = 0.032], Hispanic vs. white [7.2% (5.3 to 9.0), P < 0.001], lower concurrent CD4 count [≤200 vs. >500 cells/mm: 2.2% (0.7 to 3.7), P < 0.001], lower concurrent CD4/CD8 ratio [-2.6% (-3.7 to -1.5) per 0.5 unit increase, P < 0.001], and higher pre-ART CD8 T-cell activation [2.0% (1.6 to 2.5) per 10% higher, P < 0.001]. CONCLUSIONS In participants included in our analysis, residual low-level viremia between 51 and 200 copies per milliliter during ART was shown to be associated with greater CD8 T-cell activation than full suppression to <50 copies per milliliter. Older age, hepatitis C virus antibody positivity, race/ethnicity, higher pre-ART CD8 T-cell activation, and lower concurrent CD4/CD8 ratio and CD4 T-cell count also contribute to greater CD8 T-cell activation during suppressive ART.
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Affiliation(s)
- Lu Zheng
- *Center for Biostatistics in AIDS Research, Harvard School of Public Health, Boston, MA; †Division of Infectious Diseases, Northwestern University, Chicago, IL; ‡Division of Infectious Diseases, Massachusetts General Hospital (MGH), Boston, MA; §The Ragon Institute of MGH, Massachusetts Institute of Technology, and Harvard, Cambridge, MA; ‖Division of HIV/AIDS, San Francisco General Hospital, University of California at San Francisco, San Francisco, CA; ¶Division of Infectious Diseases; Department of Medicine; University of Washington, Seattle, WA; #Division of Clinical Pharmacology, School of Medicine, Johns Hopkins University, Baltimore, MD; and **Center for Biostatistics in AIDS Research, Harvard School of Public Health, Boston, MA
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Ouédraogo DD, Sawadogo LM, Sagna Y, Sawadogo AB, Diallo I, Hema A, Poda A, Drabo YJ. Risk Factors for Early Mortality on Antiretroviral Treatment of Elderly People Infected with HIV in Burkina Faso. J Int Assoc Provid AIDS Care 2014; 14:553-9. [PMID: 25294855 DOI: 10.1177/2325957414553841] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
BACKGROUND Age is a key determinant of mortality due to diseases including HIV infection. METHODS A retrospective and descriptive cohort study used a computerized database to compare HIV-infected patients diagnosed in late adulthood to a group of patients diagnosed before their 49 years of age, without matching the characteristics of HIV infection. The study included patients who visited the day hospital (outpatient clinic) of the Sanou Souro Teaching Hospital of Bobo-Dioulasso, in Burkina Faso, from January 2007 to December 2011. Older adults were defined as those aged 50 years and more. RESULTS Participants in the study consisted of 2572 patients (265 older adults and 2307 young patients living with HIV. Based on Markov chain method, 32.1% of the older adults living with HIV were found to be seroconvert at 50 years or older. The median follow-up time on antiretroviral treatment (ART) was 32.7 months (range 0.03-65.4 months). Two hundred and ninety-five (11.5%) patients died, including 21.1% of older adults and 10.4% of young (P < .01). World Health Organization stage 3 or 4 and the lowest CD4 count reached <200 cells/mm(3) were the factors associated with early mortality of older adults on ART. CONCLUSION Mortality rate of older adult patients living with HIV in Burkina Faso is high. Early diagnosis, early treatment, and primary prevention of HIV infection in the older adults are the main keys that could help reduce such mortality.
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Affiliation(s)
- Dieu-Donné Ouédraogo
- Internal Medicine Department, Yalgado Ouédraogo Teaching Hospital, Ouagadougou, Burkina Faso
| | - Lynda Magali Sawadogo
- Internal Medicine Department, Yalgado Ouédraogo Teaching Hospital, Ouagadougou, Burkina Faso
| | - Yempabou Sagna
- Internal Medicine Department, Yalgado Ouédraogo Teaching Hospital, Ouagadougou, Burkina Faso
| | - Adrien B Sawadogo
- Infectious Department, Sanou Souro Teaching Hospital, Bobo-Dioulasso, Burkina Faso
| | - Ismael Diallo
- Internal Medicine Department, Yalgado Ouédraogo Teaching Hospital, Ouagadougou, Burkina Faso
| | - Arsène Hema
- Infectious Department, Sanou Souro Teaching Hospital, Bobo-Dioulasso, Burkina Faso
| | - Armel Poda
- Infectious Department, Sanou Souro Teaching Hospital, Bobo-Dioulasso, Burkina Faso
| | - Youssouf Joseph Drabo
- Internal Medicine Department, Yalgado Ouédraogo Teaching Hospital, Ouagadougou, Burkina Faso
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Van Epps P, Matining RM, Tassiopoulos K, Anthony DD, Landay A, Kalayjian RC, Canaday DH. Older age is associated with peripheral blood expansion of naïve B cells in HIV-infected subjects on antiretroviral therapy. PLoS One 2014; 9:e107064. [PMID: 25207968 PMCID: PMC4160206 DOI: 10.1371/journal.pone.0107064] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2014] [Accepted: 08/06/2014] [Indexed: 01/12/2023] Open
Abstract
Older HIV infected subjects were previously found to have significant B cell expansion during initial antiretroviral therapy in a prospective age-differentiated cohort of older and younger (≥45 vs. ≤30 years) HIV-infected subjects initiating antiretroviral therapy (ART) through the AIDS Clinical Trials Group. Here to further describe this expansion, using a subset of subjects from the same cohort, we characterized B cell phenotypes at baseline and after 192 weeks of ART in both older and younger HIV-infected groups and compared them to uninfected age-matched controls. We also examined whether phenotypes at baseline associated with response to tetanus and hepatitis A vaccine at 12 weeks. Forty six subjects were analyzed in the HIV infected group (21 older, 25 younger) and 30 in the control group (15 per age group). We observed naïve B cells to normalize in younger subjects after 192 weeks of ART, while in older subjects naïve B cells increased to greater levels than those of controls (p = 0.045). Absolute resting memory (RM) cell count was significantly lower in the older HIV infected group at baseline compared to controls and numbers normalized after 192 weeks of ART (p<0.001). Baseline RM cell count positively correlated with week 12 increase in antibody to tetanus vaccine among both younger and older HIV-infected subjects combined (p = 0.01), but not in controls. The age-associated naïve B cell expansion is a novel finding and we discuss several possible explanations for this observation. Relationship between RM cells at baseline and tetanus responses may lead to insights about the effects of HIV infection on B cell memory function and vaccine responses.
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Affiliation(s)
- Puja Van Epps
- Geriatric Research Center Clinical Core (GRECC), Department of Infectious Diseases, Louis Stokes Cleveland VA Medical Center, Case Western Reserve University, Cleveland, Ohio, United States of America
- * E-mail:
| | - Roy M. Matining
- Harvard School of Public Health, Boston, Massachusetts, United States of America
| | | | - Donald D. Anthony
- Geriatric Research Center Clinical Core (GRECC), Department of Infectious Diseases, Louis Stokes Cleveland VA Medical Center, Case Western Reserve University, Cleveland, Ohio, United States of America
| | - Alan Landay
- Department of Immunology and Microbiology, Rush Medical Center, Chicago, Illinois, United States of America
| | - Robert C. Kalayjian
- Department of Infectious Diseases, Metrohealth Medical Center, Cleveland, Ohio, United States of America, and Geriatric Research Center Clinical Core (GRECC), Louis Stokes Cleveland VA Medical Center, Cleveland, Ohio, United States of America
| | - David H. Canaday
- Geriatric Research Center Clinical Core (GRECC), Department of Infectious Diseases, Louis Stokes Cleveland VA Medical Center, Case Western Reserve University, Cleveland, Ohio, United States of America
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Abstract
OBJECTIVE Low CD4/CD8 T-cell ratios occur in conditions associated with reduced immune resilience, including older age and HIV infection. Effective antiretroviral therapy increases CD4/CD8 T-cell ratios, but often not to preinfection levels. The reasons for this deficit remain unclear. As cytomegalovirus (CMV) infection exacerbates falling CD4/CD8 T-cell ratios and immune senescence in the old elderly population, we investigated whether CMV infection is associated with refractory inversion of CD4/CD8 T-cell ratios and increased phenotypic evidence of immune senescence in HIV infection. DESIGN An observational cohort study of HIV-infected individuals attending the Newfoundland and Labrador Provincial HIV Clinic in St. John's. METHODS CMV infection status was determined by ELISA with infected cell lysate. Expression of CD28 and CD57 on CD8 T cells and cellular immune responses against CMV were measured by flow cytometry. We compared CD4/CD8 T-cell ratios, percentage of CD8 T cells expressing CD28 and percentage of CD8 T cells expressing CD57 between groups of HIV-infected persons discordant for CMV infection. RESULTS The CMV-seronegative group had significantly higher CD4/CD8 T-cell ratios, more frequent normalization of the ratio to at least 1, and lesser phenotypic evidence of immune senescence. CONCLUSION CMV infection is associated with reduced immune reconstitution in HIV infection, even with suppression of HIV replication below detectable levels. This suggests that CMV infection, or some related factor, influences immune resilience in the setting of HIV infection.
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Bernard MA, Han X, Inderbitzin S, Agbim I, Zhao H, Koziel H, Tachado SD. HIV-derived ssRNA binds to TLR8 to induce inflammation-driven macrophage foam cell formation. PLoS One 2014; 9:e104039. [PMID: 25090652 PMCID: PMC4121254 DOI: 10.1371/journal.pone.0104039] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2014] [Accepted: 07/04/2014] [Indexed: 01/12/2023] Open
Abstract
Even though combined anti-retroviral therapy (cART) dramatically improves patient survival, they remain at a higher risk of being afflicted with non-infectious complications such as cardiovascular disease (CVD). This increased risk is linked to persistent inflammation and chronic immune activation. In this study, we assessed whether this complication is related to HIV-derived ssRNAs inducing in macrophages increases in TNFα release through TLR8 activation leading to foam cell formation. HIV ssRNAs induced foam cell formation in monocyte-derived macrophages (MDMs) in a dose-dependent manner. This response was reduced when either endocytosis or endosomal acidification was inhibited by dynasore or chloroquine, respectively. Using a flow cytometry FRET assay, we demonstrated that ssRNAs bind to TLR8 in HEK cells. In MDMs, ssRNAs triggered a TLR8-mediated inflammatory response that ultimately lead to foam cell formation. Targeted silencing of the TLR8 and MYD88 genes reduced foam cell formation. Furthermore, foam cell formation induced by these ssRNAs was blocked by an anti-TNFα neutralizing antibody. Taken together in MDMs, HIV ssRNAs are internalized; bind TLR8 in the endosome followed by endosomal acidification. TLR8 signaling then triggers TNFα release and ultimately leads to foam cell formation. As this response was inhibited by a blocking anti-TNFα antibody, drug targeting HIV ssRNA-driven TLR8 activation may serve as a potential therapeutic target to reduce chronic immune activation and inflammation leading to CVD in HIV+ patients.
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Affiliation(s)
- Mark A. Bernard
- Division of Pulmonary, Critical Care, and Sleep Medicine; Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States of America
| | - Xinbing Han
- Division of Pulmonary, Critical Care, and Sleep Medicine; Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States of America
| | - Sonya Inderbitzin
- Division of Pulmonary, Critical Care, and Sleep Medicine; Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States of America
| | - Ifunanya Agbim
- Division of Pulmonary, Critical Care, and Sleep Medicine; Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States of America
| | - Hui Zhao
- Division of Pulmonary, Critical Care, and Sleep Medicine; Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States of America
- From Department of Respiratory Medicine, The Second Hospital of Shanxi Medical University, Taiyuan, PR China
| | - Henry Koziel
- Division of Pulmonary, Critical Care, and Sleep Medicine; Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States of America
| | - Souvenir D. Tachado
- Division of Pulmonary, Critical Care, and Sleep Medicine; Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States of America
- * E-mail:
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De Pablo-Bernal RS, Ruiz-Mateos E, Rosado I, Dominguez-Molina B, Alvarez-Ríos AI, Carrillo-Vico A, De La Rosa R, Delgado J, Muñoz-Fernández MA, Leal M, Ferrando-Martínez S. TNF-α levels in HIV-infected patients after long-term suppressive cART persist as high as in elderly, HIV-uninfected subjects. J Antimicrob Chemother 2014; 69:3041-6. [PMID: 25011654 DOI: 10.1093/jac/dku263] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
BACKGROUND Chronic and systemic inflammatory alterations occur in HIV-infected patients and elderly uninfected subjects and in both scenarios these alterations are associated with the development of chronic morbidities and mortality. However, whether the levels of inflammatory alterations in untreated HIV-infected patients and elderly individuals are similar is unknown. Moreover, whether long-term antiretroviral therapy normalizes inflammatory alterations compared with HIV-uninfected persons of different age is not known. METHODS We analysed soluble inflammatory levels [high-sensitivity C-reactive protein, interferon (IFN)-γ, tumour necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-8 and IL-17] in a cohort of viraemic HIV-infected patients compared with (i) age-matched, (ii) elderly and (iii) non-survivor elderly, uninfected healthy controls. We longitudinally analysed the effect of long-term 48 and 96 week suppressive combined antiretroviral therapy (cART) on the soluble inflammatory levels compared with those found in control subjects. RESULTS Baseline IL-6 and IL-8 levels were at similar or lower concentrations in untreated patients compared with healthy elderly individuals. However, TNF-α and IFN-γ levels broadly exceeded those found in survivors and non-survivor elderly individuals. Long-term suppressive cART normalized most of the inflammatory markers, with the exception of TNF-α levels, which persisted as high as those in elderly non-survivor controls. CONCLUSIONS Chronic inflammatory alterations associated with HIV infection are maintained at a different level from those of ageing. The persistent alteration of TNF-α levels in HIV-infected patients might cause tissue damage and have implications for developing non-AIDS-defining illnesses, even when HIV replication is long-term controlled by cART.
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Affiliation(s)
- R S De Pablo-Bernal
- Laboratory of Immunovirology, Clinic Unit of Infectious Diseases, Microbiology and Preventive Medicine, Institute of Biomedicine of Seville, IBiS, Virgen del Rocío University Hospital/CSIC/University of Seville, Seville, Spain
| | - E Ruiz-Mateos
- Laboratory of Immunovirology, Clinic Unit of Infectious Diseases, Microbiology and Preventive Medicine, Institute of Biomedicine of Seville, IBiS, Virgen del Rocío University Hospital/CSIC/University of Seville, Seville, Spain
| | - I Rosado
- Laboratory of Immunovirology, Clinic Unit of Infectious Diseases, Microbiology and Preventive Medicine, Institute of Biomedicine of Seville, IBiS, Virgen del Rocío University Hospital/CSIC/University of Seville, Seville, Spain
| | - B Dominguez-Molina
- Laboratory of Immunovirology, Clinic Unit of Infectious Diseases, Microbiology and Preventive Medicine, Institute of Biomedicine of Seville, IBiS, Virgen del Rocío University Hospital/CSIC/University of Seville, Seville, Spain
| | - A I Alvarez-Ríos
- Department of Clinical Biochemistry, Institute of Biomedicine of Seville, IBiS, Virgen del Rocío University Hospital IBiS/CSIC/University of Seville, Seville, Spain
| | - A Carrillo-Vico
- Department of Medical Biochemistry and Molecular Biology and Immunology, University of Seville School of Medicine, Institute of Biomedicine of Seville, IBiS, Virgen del Rocío University Hospital/CSIC/University of Seville and Red Temática de Investigación Cooperativa en Envejecimiento y Fragilidad (RETICEF)-Instituto de Salud Carlos III, Seville, Spain
| | - R De La Rosa
- Internal Medicine Service, San Juan de Dios Hospital, Bormujos, Seville, Spain
| | - J Delgado
- Laboratory of Molecular Immuno-Biology, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - M A Muñoz-Fernández
- Laboratory of Molecular Immuno-Biology, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - M Leal
- Laboratory of Immunovirology, Clinic Unit of Infectious Diseases, Microbiology and Preventive Medicine, Institute of Biomedicine of Seville, IBiS, Virgen del Rocío University Hospital/CSIC/University of Seville, Seville, Spain
| | - S Ferrando-Martínez
- Laboratory of Molecular Immuno-Biology, Hospital General Universitario Gregorio Marañón, Madrid, Spain
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47
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Zheng HY, Zhang MX, Pang W, Zheng YT. Aged Chinese rhesus macaques suffer severe phenotypic T- and B-cell aging accompanied with sex differences. Exp Gerontol 2014; 55:113-9. [DOI: 10.1016/j.exger.2014.04.004] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2013] [Revised: 04/05/2014] [Accepted: 04/08/2014] [Indexed: 10/25/2022]
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48
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Lee SA, Sinclair E, Jain V, Huang Y, Epling L, Van Natta M, Meinert CL, Martin JN, McCune JM, Deeks SG, Lederman MM, Hecht FM, Hunt PW. Low proportions of CD28- CD8+ T cells expressing CD57 can be reversed by early ART initiation and predict mortality in treated HIV infection. J Infect Dis 2014; 210:374-82. [PMID: 24585893 DOI: 10.1093/infdis/jiu109] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND Unlike cytomegalovirus (CMV) infection and aging, human immunodeficiency virus (HIV) decreases the proportion of CD28(-)CD8(+) T cells expressing CD57. Whether this abnormality predicts mortality in treated HIV infection and can be reversed by early antiretroviral therapy (ART) remains unknown. METHODS We sampled recently HIV-infected individuals (<6 months) and HIV-uninfected controls and compared longitudinal changes in the proportion of CD28(-)CD8(+) T cells expressing CD57 between those who initiated ART early (<6 months) vs later (≥2 years). We also assessed the relationship between this phenotype and mortality in a nested case-control study of ART-suppressed chronically infected individuals. RESULTS Compared to HIV-uninfected controls (n = 15), individuals who were recently infected with HIV had lower proportions of CD28(-)CD8(+) T cells expressing CD57 (P < .001), and these proportions increased during ART. The early ART group (n = 33) achieved normal levels, whereas the later ART group (n = 30) continued to have lower levels than HIV-uninfected controls (P = .02). Among 141 ART-suppressed participants in the SOCA study, those in the lowest quartile of CD28(-)CD8(+) T cells expressing CD57 had 5-fold higher odds of mortality than those in the highest quartile (95% CI, 1.6-15.9, P = .007). CONCLUSIONS Abnormally low proportions of CD28(-)CD8(+) T cells expressing CD57 predict increased mortality during treated HIV infection and may be reversed with early ART initiation.
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Affiliation(s)
- Sulggi A Lee
- University of California San Francisco, San Francisco, California
| | | | - Vivek Jain
- University of California San Francisco, San Francisco, California
| | - Yong Huang
- University of California San Francisco, San Francisco, California
| | - Lorrie Epling
- University of California San Francisco, San Francisco, California
| | | | | | - Jeffrey N Martin
- University of California San Francisco, San Francisco, California
| | - Joseph M McCune
- University of California San Francisco, San Francisco, California
| | - Steven G Deeks
- University of California San Francisco, San Francisco, California
| | | | | | - Peter W Hunt
- University of California San Francisco, San Francisco, California
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49
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Buggert M, Frederiksen J, Noyan K, Svärd J, Barqasho B, Sönnerborg A, Lund O, Nowak P, Karlsson AC. Multiparametric bioinformatics distinguish the CD4/CD8 ratio as a suitable laboratory predictor of combined T cell pathogenesis in HIV infection. THE JOURNAL OF IMMUNOLOGY 2014; 192:2099-108. [PMID: 24493822 DOI: 10.4049/jimmunol.1302596] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
HIV disease progression is characterized by numerous pathological changes of the cellular immune system. Still, the CD4 cell count and viral load represent the laboratory parameters that are most commonly used in the clinic to determine the disease progression. In this study, we conducted an interdisciplinary investigation to determine which laboratory parameters (viral load, CD4 count, CD8 count, CD4 %, CD8 %, CD4/CD8) are most strongly associated with pathological changes of the immune system. Multiparametric flow cytometry was used to assess markers of CD4(+) and CD8(+) T cell activation (CD38, HLA-DR), exhaustion (PD-1, Tim-3), senescence (CD28, CD57), and memory differentiation (CD45RO, CD27) in a cohort of 47 untreated HIV-infected individuals. Using bioinformatical methods, we identified 139 unique populations, representing the "combined T cell pathogenesis," which significantly differed between the HIV-infected individuals and healthy control subjects. CD38, HLA-DR, and PD-1 were particularly expressed within these unique T cell populations. The CD4/CD8 ratio was correlated with more pathological T cell populations (n = 10) and had a significantly higher average correlation coefficient than any other laboratory parameters. We also reduced the dimensionalities of the 139-unique populations by Z-transformations and principal component analysis, which still identified the CD4/CD8 ratio as the preeminent surrogate of combined T cell pathogenesis. Importantly, the CD4/CD8 ratio at baseline was shown to be significantly associated with CD4 recovery 2 y after therapy initiation. These results indicate that the CD4/CD8 ratio would be a suitable laboratory predictor in future clinical and therapeutic settings to monitor pathological T cell events in HIV infection.
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Affiliation(s)
- Marcus Buggert
- Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, S-141 86 Stockholm, Sweden
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50
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Emu B, Moretto WJ, Hoh R, Krone M, Martin JN, Nixon DF, Deeks SG, McCune JM. Composition and function of T cell subpopulations are slow to change despite effective antiretroviral treatment of HIV disease. PLoS One 2014; 9:e85613. [PMID: 24465619 PMCID: PMC3897457 DOI: 10.1371/journal.pone.0085613] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2013] [Accepted: 12/05/2013] [Indexed: 11/18/2022] Open
Abstract
The ability to reconstitute a normal immune system with antiretroviral therapy in the setting of HIV infection remains uncertain. This study aimed to characterize quantitative and qualitative aspects of various T cell subpopulations that do not improve despite effective ART. CD4∶CD8 ratio was evaluated in HIV-infected subjects with viral loads >10,000 copies/µl (“non-controllers”, n = 42), those with undetectable viral loads on ART (“ART-suppressed”, n = 53), and HIV-uninfected subjects (n = 22). In addition, T cell phenotype and function were examined in 25 non-controllers, 18 ART-suppressed, and 7 HIV-uninfected subjects. CD4∶CD8 ratio in non-controllers, ART-suppressed, and HIV-uninfected subjects was 0.25, 0.48, and 1.95 respectively (P<0.0001 for all comparisons). The increased ratio in ART-suppressed compared to non-controllers was driven by an increase of CD4+ T cells, with no change in the expanded CD8+ T cell population. Expansion of differentiated (CD28−CD27−CD45RA+/−CCR7−) T cell subpopulations persisted despite ART and minimal changes were noted in naïve T cell frequencies over time. Increased number of CD8+CD28− T cells and increased CD8+ CMV-specific T cell responses were associated with a decreased CD4∶CD8 ratio. Measures of T cell function demonstrated persistence of high frequencies of CD8+ T cells producing IFN–γ. Lastly, though all CD8+ subpopulations demonstrated significantly lower Ki67 expression in ART-suppressed subjects, CD4+ T cell subpopulations did not consistently show this decrease, thus demonstrating different proliferative responses in the setting of T cell depletion. In summary, this study demonstrated that CD4∶CD8 ratios remained significantly decreased and naïve T cell numbers were slow to increase despite long-term viral suppression on ART. In addition, there is a evidence of differential regulation of the CD4+ and CD8+ T cell subpopulations, suggesting independent homeostatic regulation of the two compartments.
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Affiliation(s)
- Brinda Emu
- Department of Medicine, Yale University, New Haven, Connecticut, United States of America
- * E-mail:
| | - Walter J. Moretto
- Gladstone Institute of Virology and Immunology, San Francisco, California, United States of America
| | - Rebecca Hoh
- Positive Health Program, University of California San Francisco, San Francisco, California, United States of America
| | - Melissa Krone
- Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, United States of America
| | - Jeffrey N. Martin
- Positive Health Program, University of California San Francisco, San Francisco, California, United States of America
- Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, United States of America
| | - Douglas F. Nixon
- Division of Experimental Medicine, University of California San Francisco, San Francisco, California, United States of America
| | - Steven G. Deeks
- Positive Health Program, University of California San Francisco, San Francisco, California, United States of America
| | - Joseph M. McCune
- Positive Health Program, University of California San Francisco, San Francisco, California, United States of America
- Division of Experimental Medicine, University of California San Francisco, San Francisco, California, United States of America
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