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1
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Gobran ST, Ancuta P, Shoukry NH. A Tale of Two Viruses: Immunological Insights Into HCV/HIV Coinfection. Front Immunol 2021; 12:726419. [PMID: 34456931 PMCID: PMC8387722 DOI: 10.3389/fimmu.2021.726419] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Accepted: 07/26/2021] [Indexed: 12/13/2022] Open
Abstract
Nearly 2.3 million individuals worldwide are coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV). Odds of HCV infection are six times higher in people living with HIV (PLWH) compared to their HIV-negative counterparts, with the highest prevalence among people who inject drugs (PWID) and men who have sex with men (MSM). HIV coinfection has a detrimental impact on the natural history of HCV, including higher rates of HCV persistence following acute infection, higher viral loads, and accelerated progression of liver fibrosis and development of end-stage liver disease compared to HCV monoinfection. Similarly, it has been reported that HCV coinfection impacts HIV disease progression in PLWH receiving anti-retroviral therapies (ART) where HCV coinfection negatively affects the homeostasis of CD4+ T cell counts and facilitates HIV replication and viral reservoir persistence. While ART does not cure HIV, direct acting antivirals (DAA) can now achieve HCV cure in nearly 95% of coinfected individuals. However, little is known about how HCV cure and the subsequent resolution of liver inflammation influence systemic immune activation, immune reconstitution and the latent HIV reservoir. In this review, we will summarize the current knowledge regarding the pathogenesis of HIV/HCV coinfection, the effects of HCV coinfection on HIV disease progression in the context of ART, the impact of HIV on HCV-associated liver morbidity, and the consequences of DAA-mediated HCV cure on immune reconstitution and HIV reservoir persistence in coinfected patients.
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Affiliation(s)
- Samaa T Gobran
- Centre de Recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada.,Département de microbiologie, infectiologie et immunologie, Faculté de Médecine, Université de Montréal, Montréal, QC, Canada.,Department of Medical Microbiology and Immunology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Petronela Ancuta
- Centre de Recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada.,Département de microbiologie, infectiologie et immunologie, Faculté de Médecine, Université de Montréal, Montréal, QC, Canada
| | - Naglaa H Shoukry
- Centre de Recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada.,Département de médecine, Faculté de médecine, Université de Montréal, Montréal, QC, Canada
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2
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Devi P, Khan A, Chattopadhyay P, Mehta P, Sahni S, Sharma S, Pandey R. Co-infections as Modulators of Disease Outcome: Minor Players or Major Players? Front Microbiol 2021; 12:664386. [PMID: 34295314 PMCID: PMC8290219 DOI: 10.3389/fmicb.2021.664386] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Accepted: 06/16/2021] [Indexed: 12/12/2022] Open
Abstract
Human host and pathogen interaction is dynamic in nature and often modulated by co-pathogens with a functional role in delineating the physiological outcome of infection. Co-infection may present either as a pre-existing pathogen which is accentuated by the introduction of a new pathogen or may appear in the form of new infection acquired secondarily due to a compromised immune system. Using diverse examples of co-infecting pathogens such as Human Immunodeficiency Virus, Mycobacterium tuberculosis and Hepatitis C Virus, we have highlighted the role of co-infections in modulating disease severity and clinical outcome. This interaction happens at multiple hierarchies, which are inclusive of stress and immunological responses and together modulate the disease severity. Already published literature provides much evidence in favor of the occurrence of co-infections during SARS-CoV-2 infection, which eventually impacts the Coronavirus disease-19 outcome. The availability of biological models like 3D organoids, mice, cell lines and mathematical models provide us with an opportunity to understand the role and mechanism of specific co-infections. Exploration of multi-omics-based interactions across co-infecting pathogens may provide deeper insights into their role in disease modulation.
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Affiliation(s)
- Priti Devi
- INtegrative GENomics of HOst-PathogEn Laboratory, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Azka Khan
- INtegrative GENomics of HOst-PathogEn Laboratory, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India
| | - Partha Chattopadhyay
- INtegrative GENomics of HOst-PathogEn Laboratory, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Priyanka Mehta
- INtegrative GENomics of HOst-PathogEn Laboratory, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India
| | - Shweta Sahni
- INtegrative GENomics of HOst-PathogEn Laboratory, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India
| | - Sachin Sharma
- INtegrative GENomics of HOst-PathogEn Laboratory, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India
| | - Rajesh Pandey
- INtegrative GENomics of HOst-PathogEn Laboratory, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
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3
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Zarini G, Sales Martinez S, Campa A, Sherman K, Tamargo J, Hernandez Boyer J, Teeman C, Johnson A, Degarege A, Greer P, Liu Q, Huang Y, Mandler R, Choi D, Baum MK. Sex Differences, Cocaine Use, and Liver Fibrosis Among African Americans in the Miami Adult Studies on HIV Cohort. J Womens Health (Larchmt) 2020; 29:1176-1183. [PMID: 32004098 DOI: 10.1089/jwh.2019.7954] [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: 12/17/2022] Open
Abstract
Background: HIV infection disproportionally affects African Americans. Liver disease is a major cause of non-HIV morbidity and mortality in this population. Substance abuse accelerates HIV disease and may facilitate progression of liver disease. This study investigated the relationship between sex differences and cocaine use with liver injury, characterized as hepatic fibrosis. Materials and Methods: A cross-sectional study was conducted on 544 African Americans [369 people living with HIV (PLWH) and 175 HIV seronegative] from the Miami Adult Studies on HIV (MASH) cohort. Cocaine use was determined with a validated self-reported questionnaire and confirmed with urine screen. Fasting blood was used to estimate liver fibrosis using the noninvasive fibrosis-4 (FIB-4) index. Results: Men living with HIV had 1.79 times higher odds for liver fibrosis than women living with HIV (p = 0.038). African American women had higher CD4 count (p = 0.001) and lower HIV viral load (p = 0.011) compared to African American men. Fewer women (PLWH and HIV seronegative) smoked cigarettes (p = 0.002), and fewer had hazardous or harmful alcohol use (p < 0.001) than men. Women also had higher body mass index (kg/m2) (p < 0.001) compared to men. No significant association was noted among HIV seronegative participants for liver fibrosis by sex differences or cocaine use. Among African Americans living with HIV, cocaine users were 1.68 times more likely to have liver fibrosis than cocaine nonusers (p = 0.044). Conclusions: Sex differences and cocaine use appear to affect liver disease among African Americans living with HIV pointing to the importance of identifying at-risk individuals to improve outcomes of liver disease.
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Affiliation(s)
- Gustavo Zarini
- Department of Dietetics and Nutrition, Florida International University, Miami, Florida, USA
| | - Sabrina Sales Martinez
- Department of Dietetics and Nutrition, Florida International University, Miami, Florida, USA
| | - Adriana Campa
- Department of Dietetics and Nutrition, Florida International University, Miami, Florida, USA
| | - Kenneth Sherman
- Division of Digestive Diseases, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Javier Tamargo
- Department of Dietetics and Nutrition, Florida International University, Miami, Florida, USA
| | | | - Colby Teeman
- Department of Dietetics and Nutrition, Florida International University, Miami, Florida, USA
| | - Angelique Johnson
- Department of Dietetics and Nutrition, Florida International University, Miami, Florida, USA
| | - Abraham Degarege
- Department of Epidemiology, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Pedro Greer
- Department of Humanities, Health and Society, Florida International University, Miami, Florida, USA
| | - Qingyun Liu
- Department of Dietetics and Nutrition, Florida International University, Miami, Florida, USA
| | - Yongjun Huang
- Department of Dietetics and Nutrition, Florida International University, Miami, Florida, USA
| | - Raul Mandler
- Center for the Clinical Trials Network, National Institute on Drug Abuse, National Institutes of Health, Bethesda, Maryland, USA
| | - David Choi
- Department of Gastroenterology, Lake Erie College of Osteopathic Medicine, Larkin Community Hospital, South Miami, Florida, USA
| | - Marianna K Baum
- Department of Dietetics and Nutrition, Florida International University, Miami, Florida, USA
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4
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Ganesan M, Poluektova LY, Kharbanda KK, Osna NA. Human immunodeficiency virus and hepatotropic viruses co-morbidities as the inducers of liver injury progression. World J Gastroenterol 2019; 25:398-410. [PMID: 30700937 PMCID: PMC6350175 DOI: 10.3748/wjg.v25.i4.398] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Revised: 01/15/2019] [Accepted: 01/18/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatotropic viruses induced hepatitis progresses much faster and causes more liver- related health problems in people co-infected with human immunodeficiency virus (HIV). Although treatment with antiretroviral therapy has extended the life expectancy of people with HIV, liver disease induced by hepatitis B virus (HBV) and hepatitis C virus (HCV) causes significant numbers of non-acquired immune deficiency syndrome (AIDS)-related deaths in co-infected patients. In recent years, new insights into the mechanisms of accelerated fibrosis and liver disease progression in HIV/HCV and HIV/HBV co-infections have been reported. In this paper, we review recent studies examining the natural history and pathogenesis of liver disease in HIV-HCV/HBV co-infection in the era of direct acting antivirals (DAA) and antiretroviral therapy (ART). We also review the novel therapeutics for management of HIV/HCV and HIV/HBV co-infected individuals.
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Affiliation(s)
- Murali Ganesan
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, United States
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68105, United States
| | - Larisa Y Poluektova
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Kusum K Kharbanda
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, United States
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68105, United States
| | - Natalia A Osna
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, United States
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68105, United States
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5
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Abstract
Exhausted CD8 T (Tex) cells are a distinct cell lineage that arise during chronic infections and cancers in animal models and humans. Tex cells are characterized by progressive loss of effector functions, high and sustained inhibitory receptor expression, metabolic dysregulation, poor memory recall and homeostatic self-renewal, and distinct transcriptional and epigenetic programs. The ability to reinvigorate Tex cells through inhibitory receptor blockade, such as αPD-1, highlights the therapeutic potential of targeting this population. Emerging insights into the mechanisms of exhaustion are informing immunotherapies for cancer and chronic infections. However, like other immune cells, Tex cells are heterogeneous and include progenitor and terminal subsets with unique characteristics and responses to checkpoint blockade. Here, we review our current understanding of Tex cell biology, including the developmental paths, transcriptional and epigenetic features, and cell intrinsic and extrinsic factors contributing to exhaustion and how this knowledge may inform therapeutic targeting of Tex cells in chronic infections, autoimmunity, and cancer.
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Affiliation(s)
- Laura M McLane
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; .,Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.,Parker Institute for Cancer Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
| | - Mohamed S Abdel-Hakeem
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; .,Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.,Parker Institute for Cancer Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.,Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University, Kasr El-Aini, Cairo 11562, Egypt
| | - E John Wherry
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; .,Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.,Parker Institute for Cancer Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
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6
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Ganesan M, Poluektova LY, Kharbanda KK, Osna NA. Liver as a target of human immunodeficiency virus infection. World J Gastroenterol 2018; 24:4728-4737. [PMID: 30479460 PMCID: PMC6235802 DOI: 10.3748/wjg.v24.i42.4728] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Revised: 10/10/2018] [Accepted: 10/21/2018] [Indexed: 02/06/2023] Open
Abstract
Liver injury is a characteristic feature of human immunodeficiency virus (HIV) infection, which is the second most common cause of mortality in HIV-infected patients. Now it is recognized that liver plays a key role in HIV infection pathogenesis. Antiretroviral therapy (ART), which suppresses HIV infection in permissive immune cells, is less effective in hepatocytes, thereby making these cells a silent reservoir of HIV infection. In addition to direct hepatotoxic effects of HIV, certain ART treatment modalities provide hepatotoxic effects. The exact mechanisms of HIV-triggered chronic hepatitis progression are not elucidated, but the liver is adversely affected by HIV-infection and liver cells are prominently involved in HIV-elicited injury. These effects are potentiated by second hits like alcohol. Here, we will focus on the incidence of HIV, clinical evidence of HIV-related liver damage, interactions between HIV and liver cells and the role of alcohol and co-infection with hepatotropic viruses in liver inflammation and fibrosis progression.
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Affiliation(s)
- Murali Ganesan
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, United States
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68105, United States
| | - Larisa Y Poluektova
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Kusum K Kharbanda
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, United States
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68105, United States
| | - Natalia A Osna
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, United States
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68105, United States
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7
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Signature molecules expressed differentially in a liver disease stage-specific manner by HIV-1 and HCV co-infection. PLoS One 2018; 13:e0202524. [PMID: 30138348 PMCID: PMC6107166 DOI: 10.1371/journal.pone.0202524] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2018] [Accepted: 08/03/2018] [Indexed: 12/20/2022] Open
Abstract
To elucidate HIV-1 co-infection-induced acceleration of HCV liver disease and identify stage-specific molecular signatures, we applied a new high-resolution molecular screen, the Affymetrix GeneChip Human Transcriptome Array (HTA2.0), to HCV-mono- and HIV/HCV-co-infected liver specimens from subjects with early and advanced disease. Out of 67,528 well-annotated genes, we have analyzed the functional and statistical significance of 75 and 28 genes expressed differentially between early and advanced stages of HCV mono- and HIV/HCV co-infected patient liver samples, respectively. We also evaluated the expression of 25 and 17 genes between early stages of mono- and co-infected liver tissues and between advanced stages of mono- and co-infected patient's samples, respectively. Based on our analysis of fold-change in gene expression as a function of disease stage (i.e., early vs. advanced), coupled with consideration of the known relevant functions of these genes, we focused on four candidate genes, ACSL4, GNMT, IFI27, and miR122, which are expressed stage-specifically in HCV mono- and HIV-1/HCV co-infective liver disease and are known to play a pivotal role in regulating HCV-mediated hepatocellular carcinoma (HCC). Our qRT-PCR analysis of the four genes in patient liver specimens supported the microarray data. Protein products of each gene were detected in the endoplasmic reticulum (ER) where HCV replication takes place, and the genes' expression significantly altered replicability of HCV in the subgenomic replicon harboring regulatory genes of the JFH1 strain of HCV in Huh7.5.1. With respect to three well-known transferrable HIV-1 viral elements-Env, Nef, and Tat-Nef uniquely augmented replicon expression, while Tat, but not the others, substantially modulated expression of the candidate genes in hepatocytic cells. Combinatorial expression of these cellular and viral genes in the replicon cells further altered replicon expression. Taken together, these results showed that HIV-1 viral proteins can exacerbate liver pathology in the co-infected patients by disparate molecular mechanisms-directly or indirectly dysregulating HCV replication, even if lack of association of HCV load and end-stage liver disease in hemophilic patients were reported, and modulating expression of hepatocellular genes critical for disease progression. These findings also provide major insights into development of stage-specific hepatocellular biomarkers for improved diagnosis and prognosis of HCV-mediated liver disease.
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8
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Debes JD, Bohjanen PR, Boonstra A. Mechanisms of Accelerated Liver Fibrosis Progression during HIV Infection. J Clin Transl Hepatol 2016; 4:328-335. [PMID: 28097102 PMCID: PMC5225153 DOI: 10.14218/jcth.2016.00034] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2016] [Revised: 10/14/2016] [Accepted: 10/21/2016] [Indexed: 12/23/2022] Open
Abstract
With the introduction of antiretroviral therapy (ART), a dramatic reduction in HIV-related morbidity and mortality has been observed. However, it is now becoming increasingly clear that liver-related complications, particularly rapid fibrosis development from ART as well as from the chronic HIV infection itself, are of serious concern to HIV patients. The pathophysiology of liver fibrosis in patients with HIV is a multifactorial process whereby persistent viral replication, and bacterial translocation lead to chronic immune activation and inflammation, which ART is unable to fully suppress, promoting production of fibrinogenic mediators and fibrosis. In addition, mitochondrial toxicity, triggered by both ART and HIV, contributes to intrahepatic damage, which is even more severe in patients co-infected with viral hepatitis. In recent years, new insights into the mechanisms of accelerated fibrosis and liver disease progression in HIV has been obtained, and these are detailed and discussed in this review.
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Affiliation(s)
- Jose D. Debes
- Department of Medicine, Division of Infectious Disease and International Medicine, University of Minnesota, Minneapolis, MN, USA
- *Correspondence to: Jose D. Debes, Department of Medicine, Division of Infectious Disease and International Medicine, University of Minnesota, 2001 6th Street SE, Minneapolis, MN 55455, USA. Tel: +1-612-624-6353, Fax: +1-612-301-1292, E-mail:
| | - Paul R. Bohjanen
- Department of Medicine, Division of Infectious Disease and International Medicine, University of Minnesota, Minneapolis, MN, USA
| | - Andre Boonstra
- Department of Gastroenterology and Hepatology, Erasmus MC, Rotterdam, The Netherlands
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9
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Campa A, Martinez SS, Sherman KE, Greer JP, Li Y, Garcia S, Stewart T, Ibrahimou B, Williams OD, Baum MK. Cocaine Use and Liver Disease are Associated with All-Cause Mortality in the Miami Adult Studies in HIV (MASH) Cohort. JOURNAL OF DRUG ABUSE 2016; 2:27. [PMID: 28540368 PMCID: PMC5439351 DOI: 10.21767/2471-853x.100036] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
OBJECTIVE Liver disease is a frequent cause of morbidity and mortality in HIV infection. We examined the relationship of cocaine use, liver disease progression and mortality in an HIV-infected cohort. METHODS Consent was obtained from 487 HIV+ participants, a subset of the Miami Adult Studies on HIV (MASH) cohort. Participants were eligible if they were followed for at least two years, completed questionnaires on demographics and illicit drug use and had complete metabolic panels, CD4 cell counts and HIV-viral loads. FIB-4 was calculated and cut-off points were used for staging liver fibrosis. Death certificates were obtained. RESULTS Participants were 65% men, 69% Black and 81% were on ART at recruitment. Cocaine was used by 32% of participants and 29% were HIV/HCV co-infected. Mean age was 46.9 ± 7.7 years, mean CD4 cell count was 501.9 ± 346.7 cells/μL and mean viral load was 2.75 ± 1.3 log10 copies/mL at baseline. During the follow-up, 27 patients died, with a mortality rate of 28.2/1000 person-year. Cocaine was used by 48% of those who died (specific mortality rate was 13/1000 person-year). Those who died were more likely to use cocaine (HR=3.8, P=0.006) and have more advanced liver fibrosis (HR=1.34, P<0.0001), adjusting for age, gender, CD4 cell count and HIV-viral load at baseline and over time. Among the HIV mono-infected participants, cocaine users were 5 times more likely to die (OR=5.09, P=0.006) than participants who did not use cocaine. CONCLUSION Cocaine use and liver fibrosis are strong and independent predictors of mortality in HIV infected and HIV/HCV co-infected adults. Effective interventions to reduce cocaine use among people living with HIV (PHLW) are needed.
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Affiliation(s)
- Adriana Campa
- Florida International University, R Stempel College of Public Health and Social Work, Miami, FL, USA
| | - Sabrina Sales Martinez
- Florida International University, R Stempel College of Public Health and Social Work, Miami, FL, USA
| | - Kenneth E Sherman
- University of Cincinnati, College of Medicine, Department of Internal Medicine, Cincinnati, Ohio, USA
| | - Joe Pedro Greer
- Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA
| | - Yinghui Li
- Florida International University, R Stempel College of Public Health and Social Work, Miami, FL, USA
| | - Stephanie Garcia
- Florida International University, R Stempel College of Public Health and Social Work, Miami, FL, USA
| | - Tiffanie Stewart
- Florida International University, R Stempel College of Public Health and Social Work, Miami, FL, USA
| | - Boubakari Ibrahimou
- Florida International University, R Stempel College of Public Health and Social Work, Miami, FL, USA
| | - O. Dale Williams
- Florida International University, R Stempel College of Public Health and Social Work, Miami, FL, USA
| | - Marianna K. Baum
- Florida International University, R Stempel College of Public Health and Social Work, Miami, FL, USA
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10
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Burke Schinkel SC, Carrasco-Medina L, Cooper CL, Crawley AM. Generalized Liver- and Blood-Derived CD8+ T-Cell Impairment in Response to Cytokines in Chronic Hepatitis C Virus Infection. PLoS One 2016; 11:e0157055. [PMID: 27315061 PMCID: PMC4912163 DOI: 10.1371/journal.pone.0157055] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2016] [Accepted: 05/24/2016] [Indexed: 12/23/2022] Open
Abstract
Generalized CD8+ T-cell impairment in chronic hepatitis C virus (HCV) infection and the contribution of liver-infiltrating CD8+ T-cells to the immunopathogenesis of this infection remain poorly understood. It is hypothesized that this impairment is partially due to reduced CD8+ T-cell activity in response to cytokines such as IL-7, particularly within the liver. To investigate this, the phenotype and cytokine responsiveness of blood- and liver-derived CD8+ T-cells from healthy controls and individuals with HCV infection were compared. In blood, IL-7 receptor α (CD127) expression on bulk CD8+ T-cells in HCV infection was no different than controls yet was lower on central memory T-cells, and there were fewer naïve cells. IL-7-induced signalling through phosphorylated STAT5 was lower in HCV infection than in controls, and differed between CD8+ T-cell subsets. Production of Bcl-2 following IL-7 stimulation was also lower in HCV infection and inversely related to the degree of liver fibrosis. In liver-derived CD8+ T-cells, STAT5 activation could not be increased with cytokine stimulation and basal Bcl-2 levels of liver-derived CD8+ T-cells were lower than blood-derived counterparts in HCV infection. Therefore, generalized CD8+ T-cell impairment in HCV infection is characterized, in part, by impaired IL-7-mediated signalling and survival, independent of CD127 expression. This impairment is more pronounced in the liver and may be associated with an increased potential for apoptosis. This generalized CD8+ T-cell impairment represents an important immune dysfunction in chronic HCV infection that may alter patient health.
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Affiliation(s)
- Stephanie C. Burke Schinkel
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada
- Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Lorna Carrasco-Medina
- Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Curtis L. Cooper
- Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
- Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, Ontario, Canada
- Division of Infectious Diseases, Ottawa Hospital-General Campus, Ottawa, Ontario, Canada
| | - Angela M. Crawley
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada
- Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
- Department of Biology, Carleton University, Ottawa, Ontario, Canada
- * E-mail:
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11
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MacParland SA, Fadel SM, Mihajlovic V, Fawaz A, Kim C, Rahman AKMNU, Liu J, Kaul R, Kovacs C, Grebely J, Dore GJ, Wong DK, Ostrowski MA. HCV Specific IL-21 Producing T Cells but Not IL-17A Producing T Cells Are Associated with HCV Viral Control in HIV/HCV Coinfection. PLoS One 2016; 11:e0154433. [PMID: 27124305 PMCID: PMC4849786 DOI: 10.1371/journal.pone.0154433] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2015] [Accepted: 04/13/2016] [Indexed: 01/17/2023] Open
Abstract
BACKGROUND Decreased hepatitis C virus (HCV) clearance, faster cirrhosis progression and higher HCV RNA levels are associated with Human Immunodeficiency virus (HIV) coinfection. The CD4+ T helper cytokines interleukin (IL)-21 and IL-17A are associated with virus control and inflammation, respectively, both important in HCV and HIV disease progression. Here, we examined how antigen-specific production of these cytokines during HCV mono and HIV/HCV coinfection was associated with HCV virus control. METHODS We measured HCV-specific IL-21 and IL-17A production by transwell cytokine secretion assay in PBMCs from monoinfected and coinfected individuals. Viral control was determined by plasma HCV RNA levels. RESULTS In acutely infected individuals, those able to establish transient/complete HCV viral control tended to have stronger HCV-specific IL-21-production than non-controllers. HCV-specific IL-21 production also correlated with HCV viral decline in acute infection. Significantly stronger HCV-specific IL-21 production was detected in HAART-treated coinfected individuals. HCV-specific IL-17A production was not associated with lower plasma HCV RNA levels in acute or chronic HCV infection and responses were stronger in HIV coinfection. HCV-specific IL-21/ IL-17A responses did not correlate with microbial translocation or fibrosis. Exogenous IL-21 treatment of HCV-specific CD8+ T cells from monoinfected individuals enhanced their function although CD8+ T cells from coinfected individuals were somewhat refractory to the effects of IL-21. CONCLUSIONS These data show that HCV-specific IL-21 and IL-17A-producing T cells are induced in HIV/HCV coinfection. In early HIV/HCV coinfection, IL-21 may contribute to viral control, and may represent a novel tool to enhance acute HCV clearance in HIV/HCV coinfected individuals.
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Affiliation(s)
- Sonya A. MacParland
- Departments of Immunology and Medicine, University of Toronto, Toronto, Ontario, Canada
- * E-mail:
| | - Saleh M. Fadel
- Departments of Immunology and Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Vesna Mihajlovic
- Departments of Immunology and Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Ali Fawaz
- Departments of Immunology and Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Connie Kim
- Departments of Immunology and Medicine, University of Toronto, Toronto, Ontario, Canada
- Toronto General Hospital, Toronto, Ontario, Canada
| | | | - Jun Liu
- Departments of Immunology and Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Rupert Kaul
- Departments of Immunology and Medicine, University of Toronto, Toronto, Ontario, Canada
- Toronto General Hospital, Toronto, Ontario, Canada
| | | | - Jason Grebely
- The Kirby Institute, UNSW Australia, Sydney, Australia
| | | | | | - Mario A. Ostrowski
- Departments of Immunology and Medicine, University of Toronto, Toronto, Ontario, Canada
- Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Toronto, Ontario, Canada
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12
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Fujita T, Burwitz BJ, Chew GM, Reed JS, Pathak R, Seger E, Clayton KL, Rini JM, Ostrowski MA, Ishii N, Kuroda MJ, Hansen SG, Sacha JB, Ndhlovu LC. Expansion of dysfunctional Tim-3-expressing effector memory CD8+ T cells during simian immunodeficiency virus infection in rhesus macaques. THE JOURNAL OF IMMUNOLOGY 2014; 193:5576-83. [PMID: 25348621 DOI: 10.4049/jimmunol.1400961] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
The T cell Ig- and mucin domain-containing molecule-3 (Tim-3) negative immune checkpoint receptor demarcates functionally exhausted CD8(+) T cells arising from chronic stimulation in viral infections like HIV. Tim-3 blockade leads to improved antiviral CD8(+) T cell responses in vitro and, therefore, represents a novel intervention strategy to restore T cell function in vivo and protect from disease progression. However, the Tim-3 pathway in the physiologically relevant rhesus macaque SIV model of AIDS remains uncharacterized. We report that Tim-3(+)CD8(+) T cell frequencies are significantly increased in lymph nodes, but not in peripheral blood, in SIV-infected animals. Tim-3(+)PD-1(+)CD8(+) T cells are similarly increased during SIV infection and positively correlate with SIV plasma viremia. Tim-3 expression was found primarily on effector memory CD8(+) T cells in all tissues examined. Tim-3(+)CD8(+) T cells have lower Ki-67 content and minimal cytokine responses to SIV compared with Tim-3(-)CD8(+) T cells. During acute-phase SIV replication, Tim-3 expression peaked on SIV-specific CD8(+) T cells by 2 wk postinfection and then rapidly diminished, irrespective of mutational escape of cognate Ag, suggesting non-TCR-driven mechanisms for Tim-3 expression. Thus, rhesus Tim-3 in SIV infection partially mimics human Tim-3 in HIV infection and may serve as a novel model for targeted studies focused on rejuvenating HIV-specific CD8(+) T cell responses.
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Affiliation(s)
- Tsuyoshi Fujita
- Department of Tropical Medicine, Hawaii Center for AIDS, John A. Burns School of Medicine, University of Hawaii, Manoa, HI 96813; Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan
| | - Benjamin J Burwitz
- Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006; Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006
| | - Glen M Chew
- Department of Tropical Medicine, Hawaii Center for AIDS, John A. Burns School of Medicine, University of Hawaii, Manoa, HI 96813
| | - Jason S Reed
- Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006; Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006
| | - Reesab Pathak
- Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006; Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006
| | - Elizabeth Seger
- Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006; Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006
| | - Kiera L Clayton
- Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada; and
| | - James M Rini
- Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada; and
| | - Mario A Ostrowski
- Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada; and
| | - Naoto Ishii
- Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan
| | - Marcelo J Kuroda
- Division of Immunology, Tulane National Primate Research Center, Covington, LA 70433
| | - Scott G Hansen
- Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006; Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006
| | - Jonah B Sacha
- Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006; Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006;
| | - Lishomwa C Ndhlovu
- Department of Tropical Medicine, Hawaii Center for AIDS, John A. Burns School of Medicine, University of Hawaii, Manoa, HI 96813;
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13
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Kared H, Saeed S, Klein MB, Shoukry NH. CD127 expression, exhaustion status and antigen specific proliferation predict sustained virologic response to IFN in HCV/HIV co-infected individuals. PLoS One 2014; 9:e101441. [PMID: 25007250 PMCID: PMC4090061 DOI: 10.1371/journal.pone.0101441] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2014] [Accepted: 06/05/2014] [Indexed: 12/31/2022] Open
Abstract
Hepatitis C virus (HCV) infection is a major cause of morbidity and mortality in the HIV co-infected population. Interferon-alpha (IFN-α) remains a major component of anti-HCV therapy despite its deleterious effects on the immune system. Furthermore, IFN-α was recently shown to diminish the size of the latent HIV reservoir. The objectives of this study were to monitor the impact of IFN-α on T cell phenotype and proliferation of HIV and HCV-specific T cells during IFN therapy, and to identify immune markers that can predict the response to IFN in HICV/HIV co-infected patients. We performed longitudinal analyses of T cell numbers, phenotype and function in co-infected patients undergoing IFN-α therapy with different outcomes including IFN-α non-responders (NR) (n = 9) and patients who achieved sustained virologic response (SVR) (n = 19). We examined the expression of activation (CD38, HLA-DR), functional (CD127) and exhaustion markers (PD1, Tim-3, CD160 and CD244) on total CD4 and CD8 T cells before, during and after therapy. In addition, we examined the HIV- and HCV-specific proliferative responses against HIV-p24 and HCV-NS3 proteins. Frequencies of CD127+ CD4 T cells were higher in SVR than in NR patients at baseline. An increase in CD127 expression on CD8 T cells was observed after IFN-α therapy in all patients. In addition, CD8 T cells from NR patients expressed a higher exhaustion status at baseline. Finally, SVR patients exhibited higher proliferative response against both HIV and HCV antigens at baseline. Altogether, SVR correlated with higher expression of CD127, lower T cell exhaustion status and better HIV and HCV proliferative responses at baseline. Such factors might be used as non-invasive methods to predict the success of IFN–based therapies in co-infected individuals.
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Affiliation(s)
- Hassen Kared
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Quebec, Canada
| | - Sahar Saeed
- Department of Medicine, Divisions of Infectious Diseases/Chronic Viral Illness Service, Royal Victoria Hospital, McGill University Health Centre, Montreal, Quebec, Canada
| | - Marina B. Klein
- Department of Medicine, Divisions of Infectious Diseases/Chronic Viral Illness Service, Royal Victoria Hospital, McGill University Health Centre, Montreal, Quebec, Canada
| | - Naglaa H. Shoukry
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Quebec, Canada
- Département de médecine, Faculté de médecine, Université de Montréal, Montréal, Quebec, Canada
- * E-mail:
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14
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HIV-1 coinfection profoundly alters intrahepatic chemokine but not inflammatory cytokine profiles in HCV-infected subjects. PLoS One 2014; 9:e86964. [PMID: 24516541 PMCID: PMC3916319 DOI: 10.1371/journal.pone.0086964] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2013] [Accepted: 12/20/2013] [Indexed: 12/11/2022] Open
Abstract
The pathogenesis of accelerated liver damage in subjects coinfected with hepatitis C virus (HCV) and human immunodeficiency virus type 1 (HIV-1) remains largely unknown. Recent studies suggest that ongoing chronic liver inflammation is responsible for the liver injury in HCV-infected patients. We aimed to determine whether HIV-1 coinfection altered intrahepatic inflammatory profiles in HCV infection, thereby hastening liver damage. We used a real-time RT-PCR-based array to comparatively analyze intrahepatic inflammation gene profiles in liver biopsy specimens from HCV-infected (n = 16), HCV/HIV-1-coinfected (n = 8) and uninfected (n = 8) individuals. We then used human hepatocytes to study the molecular mechanisms underlying alternations of the inflammatory profiles. Compared with uninfected individuals, HCV infection and HCV/HIV-1 coinfection markedly altered expression of 59.5% and 50.0% of 84 inflammation-related genes tested, respectively. Among these genes affected, HCV infection up-regulated the expression of 24 genes and down-regulated the expression of 26 genes, whereas HCV/HIV-1 coinfection up-regulated the expression of 21 genes and down-regulated the expression of 21 genes. Compared with HCV infection, HCV/HIV-1 coinfection did not dramatically affect intrahepatic gene expression profiles of cytokines and their receptors, but profoundly altered expression of several chemokine genes including up-regulation of the CXCR3-associated chemokines. Human hepatocytes produced these chemokines in response to virus-related microbial translocation, viral protein stimulation, and antiviral immune responses. Conclusions HIV-1 coinfection profoundly alters intrahepatic chemokine but not cytokine profiles in HCV-infected subjects. The altered chemokines may orchestrate the tissue-specific and cell-selective trafficking of immune cells and autoimmunity to accelerate liver disease in HCV/HIV-1 coinfection.
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16
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MacParland SA, Vali B, Ostrowski MA. Immunopathogenesis of HIV/hepatitis C virus coinfection. Future Virol 2011. [DOI: 10.2217/fvl.11.80] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
As a result of shared infection routes, approximately 25% of individuals infected with HIV in North America are also infected with hepatitis C virus (HCV). In the setting of HIV coinfection, the course of HCV disease is more aggressive, resulting in higher HCV viral loads and a more rapid progression of liver pathology. With the success of HAART, HCV-related end-stage liver disease has become a leading cause of morbidity and mortality in HIV/HCV-coinfected patients. In this article, we will discuss recent studies examining the immune response during HIV and HCV coinfection, focusing on alterations or dysfunctions in virus-specific T-cell responses that may play a role in the immunopathogenesis of HIV/HCV coinfection. Summarizing the impact of HIV coinfection on HCV-specific T-cell immunity and highlighting some of the proposed mechanisms of T-cell dysfunction in HIV/HCV-coinfected individuals may uncover information that could lead to new treatment strategies for these patients experiencing accelerated liver disease and generally poorer outcomes than their HCV-monoinfected counterparts.
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Affiliation(s)
| | - Bahareh Vali
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
| | - Mario A Ostrowski
- Department of Immunology, University of Toronto, Toronto, ON, Canada; University of Toronto, Medical Sciences Building, 1 King’s College Circle, Toronto, ON M5S 1A8, Canada
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
- Clinical Sciences Division, University of Toronto, Toronto, ON, Canada
- Li Ka Shing Knowledge Institute at St Michael’s Hospital, Toronto, ON, Canada
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17
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Down-regulation of intra-hepatic T-cell signaling associated with GB virus C in a HCV/HIV co-infected group with reduced liver disease. J Hepatol 2011; 55:536-544. [PMID: 21266183 DOI: 10.1016/j.jhep.2010.12.021] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2010] [Revised: 12/08/2010] [Accepted: 12/14/2010] [Indexed: 01/04/2023]
Abstract
BACKGROUND & AIMS Studies have shown that GB virus C (GBV-C) infection leads to reduced liver disease in hepatitis C virus (HCV)/human immunodeficiency virus (HIV) co-infection. Considering that the underlying mechanism(s) are unknown, we aim to identify differential gene and protein expression associated with GBV-C in HCV/HIV co-infection that may be responsible for reduced liver disease. METHODS Liver, peripheral blood mononuclear cells (PBMCs), and plasma samples were collected from 43 HCV/HIV patients. Plasma was tested for GBV-C RNA by RT-PCR with NS5B gene primers. A microarray was performed on the liver and RT-qPCRs on the liver/PBMC samples. Hepatic protein expression was measured by immunohistochemistry. RESULTS Sixteen out of 43 patients had GBV-C RNA. GBV-C was associated with reduced hepatic fibrosis (p=0.005) and inflammation (p=0.007). The microarray analysis of the liver samples (n=10) showed down-regulation of genes critical to intra-hepatic T-cell signaling associated with GBV-C. Quantitative RT-PCR of the liver samples (n=13) confirmed the down-regulation of lymphocyte-specific protein tyrosine kinase (LCK) (p=0.02) and docking protein 2 (DOK2) (p=0.04). No differences in the expression levels of these genes were observed in PBMCs (n=22) according to the GBV-C status. The hepatic expression of the LCK protein, measured by immunohistochemistry (n=36), was decreased in CD3-positive T-cells within portal tracts associated with GBV-C (p=0.003). This remained significant in multivariate analysis controlling for hepatic fibrosis and inflammation (p=0.027). No differences were observed in plasma cytokine concentrations (n=25) or ex-vivo peripheral T-cell responses (n=13) versus GBV-C status. CONCLUSIONS GBV-C infection is associated with down-regulation of critical genes involved in intra-hepatic T-cell signaling in HCV/HIV co-infection. This may be relevant to the pathogenesis of reduced HCV-related liver disease in HIV co-infection.
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18
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Loko MA, Bani-Sadr F, Winnock M, Lacombe K, Carrieri P, Neau D, Morlat P, Serfaty L, Dabis F, Salmon D. Impact of HAART exposure and associated lipodystrophy on advanced liver fibrosis in HIV/HCV-coinfected patients. J Viral Hepat 2011; 18:e307-14. [PMID: 21692942 DOI: 10.1111/j.1365-2893.2010.01417.x] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The impact of antiretroviral drug exposure and associated lipodystrophy and/or insulin resistance (IR) on advanced liver fibrosis in HIV/HCV-coinfected patients is not fully documented. We determined the prevalence of advanced liver fibrosis (defined by hepatic stiffness ≥9.5 kPa) and associated factors, focusing on the impact of highly active antiretroviral therapy and its major adverse effects (lipodystrophy and IR), in 671 HIV/HCV-coinfected patients included in the ANRS CO13 HEPAVIH cohort. One hundred ninety patients (28.3%) had advanced liver fibrosis. In univariate analysis, advanced liver fibrosis was significantly associated with male sex, higher body mass index, HCV infection through intravenous drug use, a lower absolute CD4 cell count, a longer history of antiretroviral treatment, longer durations of protease inhibitors, non-nucleoside reverse transcriptase inhibitors and NRTI exposure, lipodystrophy, diabetes, and a high homeostasis model assessment method (HOMA) value. The only antiretroviral drugs associated with advanced liver fibrosis were efavirenz, stavudine and didanosine. In multivariate analysis, male sex (OR 2.0, 95% CI 1.1-3.5; P = 0.018), HCV infection through intravenous drug use (OR 2.0, 95% CI 1.1-3.6; P = 0.018), lipodystrophy (OR 2.0, 95% CI 1.2-3.3; P = 0.01), median didanosine exposure longer than 5 months (OR 1.7, 95% CI 1.0-2.8; P = 0.04) and a high HOMA value (OR 1.1, 95% CI 1.0-1.2; P = 0.005) remained significantly associated with advanced liver fibrosis. Mitochondrial toxicity and IR thus appear to play a key role in liver damage associated with HIV/HCV-coinfection, and this should be taken into account when selecting and optimizing antiretroviral therapy. Antiretroviral drugs with strong mitochondrial toxicity (e.g. didanosine) or a major effect on glucose metabolism should be avoided.
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Affiliation(s)
- M A Loko
- INSERM, U897, ISPED, Université Victor Segalen, Bordeaux, France
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Operskalski EA, Kovacs A. HIV/HCV co-infection: pathogenesis, clinical complications, treatment, and new therapeutic technologies. Curr HIV/AIDS Rep 2011; 8:12-22. [PMID: 21221855 PMCID: PMC3035774 DOI: 10.1007/s11904-010-0071-3] [Citation(s) in RCA: 159] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
World-wide, hepatitis C virus (HCV) accounts for approximately 130 million chronic infections, with an overall 3% prevalence. Four to 5 million persons are co-infected with HIV. It is well established that HIV has a negative impact on the natural history of HCV, including a higher rate of viral persistence, increased viral load, and more rapid progression to fibrosis, end-stage liver disease, and death. Whether HCV has a negative impact on HIV disease progression continues to be debated. However, following the introduction of effective combination antiretroviral therapy, the survival of coinfected individuals has significantly improved and HCV-associated diseases have emerged as the most important co-morbidities. In this review, we summarize the newest studies regarding the pathogenesis of HIV/HCV coinfection, including effects of coinfection on HIV disease progression, HCV-associated liver disease, the immune system, kidney and cardiovascular disease, and neurologic status; and effectiveness of current anti-HIV and HCV therapies and proposed new treatment strategies.
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Affiliation(s)
- Eva A. Operskalski
- Maternal Child and Adolescent Center for Infectious Diseases and Virology, Department of Pediatrics, Keck School of Medicine, University of Southern California, 1640 Marengo Street, HRA 300, Los Angeles, CA 90033 USA
| | - Andrea Kovacs
- Maternal Child and Adolescent Center for Infectious Diseases and Virology, Department of Pediatrics, Keck School of Medicine, University of Southern California, 1640 Marengo Street, HRA 300, Los Angeles, CA 90033 USA
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20
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Vali B, Jones RB, Sakhdari A, Sheth PM, Clayton K, Yue FY, Gyenes G, Wong D, Klein MB, Saeed S, Benko E, Kovacs C, Kaul R, Ostrowski MA. HCV-specific T cells in HCV/HIV co-infection show elevated frequencies of dual Tim-3/PD-1 expression that correlate with liver disease progression. Eur J Immunol 2010; 40:2493-505. [PMID: 20623550 DOI: 10.1002/eji.201040340] [Citation(s) in RCA: 79] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Co-infection of HCV with HIV has been associated with more rapid progression of HCV-related disease. HCV-specific T-cell immune responses, which are essential for disease control, are attenuated in co-infection with HIV. T-cell exhaustion has recently been implicated in the deficient control of chronic viral infections. In the current study, we investigated the role of programmed death-1 (PD-1) and T-cell immunoglobulin and mucin domain-containing molecule-3 (Tim-3) expression in T-cell exhaustion during HCV/HIV co-infection. We show that in HCV/HIV co-infection, both total and HCV-specific T cells co-express Tim-3 and PD-1 in significantly higher frequencies, compared with HCV mono-infection. Co-expression of these two markers on HCV-specific CD8(+) T cells positively correlated with a clinical parameter of liver disease progression. HCV-specific CD8(+) T cells showed greater frequencies of Tim-3/PD-1 co-expression than HIV-specific CD8(+) T cells, which may indicate a greater degree of exhaustion in the former. Blocking Tim-3 or PD-1 pathways restored both HIV- and HCV-specific CD8(+) T-cell expansion in the blood of co-infected individuals. These data demonstrate that co-expression of Tim-3 and PD-1 may play a significant role in HCV-specific T-cell dysfunction, especially in the setting of HIV co-infection.
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Affiliation(s)
- Bahareh Vali
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
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21
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Characterization of cross-reactive CD8+ T-cell recognition of HLA-A2-restricted HIV-Gag (SLYNTVATL) and HCV-NS5b (ALYDVVSKL) epitopes in individuals infected with human immunodeficiency and hepatitis C viruses. J Virol 2010; 85:254-63. [PMID: 20980521 DOI: 10.1128/jvi.01743-10] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
The immunologic mechanisms underlying the faster progression of hepatitis C virus (HCV) disease in the presence of human immunodeficiency virus (HIV) coinfection are not clearly understood. T-cell cross-reactivity between HCV and influenza virus-specific epitopes has been associated with rapid progression of HCV disease (S. Urbani, B. Amadei, P. Fisicaro, M. Pilli, G. Missale, A. Bertoletti, and C. Ferrari, J. Exp. Med. 201:675-680, 2005). We asked whether T-cell cross-reactivity between HCV and HIV could exist during HCV/HIV coinfection and affect pathogenesis. Our search for amino acid sequence homology between the HCV and HIV proteomes revealed two similar HLA-A2-restricted epitopes, HIV-Gag (SLYNTVATL [HIV-SL9]) and HCV-NS5b (ALYDVVSKL [HCV-AL9]). We found that 4 out of 20 HLA-A2-positive (HLA-A2(+)) HIV-infected individuals had CD8(+) T cells that recognized both the HIV-SL9 and HCV-AL9 epitopes. However, the AL9 epitope was generally shown to be a weak agonist. Although HCV-monoinfected individuals in our study did not show AL9-specific responses, we found that about half of HCV/HIV-coinfected individuals had dual responses to both epitopes. High dual T-cell recognition among coinfected subjects was usually due to separate T-cell populations targeting each epitope, as determined by pentamer staining. The one individual demonstrating cross-reactive T cells to both epitopes showed the most advanced degree of liver disease. In coinfected individuals, we observed a positive correlation between the magnitudes of T-cell responses to both the SL9 and the AL9 epitopes, which was also positively associated with the clinical parameter of liver damage. Thus, we find that HIV infection induces T cells that can cross-react to heterologous viruses or prime for T cells that are closely related in sequence. However, the induction of cross-reactive T cells may not be associated with control of disease caused by the heterologous virus. This demonstrates that degeneracy of HIV-specific T cells may play a role in the immunopathology of HCV/HIV coinfection.
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22
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Bani-Sadr F. [ANRS HC 02 RIBAVIC: summary and recommandations]. ACTA ACUST UNITED AC 2010; 33 Suppl 2:S104-5. [PMID: 19375036 DOI: 10.1016/s0399-8320(09)72448-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Affiliation(s)
- Firouzé Bani-Sadr
- Groupe Hospitalier Universitaire Est- Hôpital Tenon-, INSERM U 707, Université Pierre et Marie Curie, Paris, France.
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23
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Immune restoration diseases reflect diverse immunopathological mechanisms. Clin Microbiol Rev 2010; 22:651-63. [PMID: 19822893 DOI: 10.1128/cmr.00015-09] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Up to one in four patients infected with human immunodeficiency virus type 1 and given antiretroviral therapy (ART) experiences inflammatory or cellular proliferative disease associated with a preexisting opportunistic infection, which may be subclinical. These immune restoration diseases (IRD) appear to result from the restoration of immunocompetence. IRD associated with intracellular pathogens are characterized by cellular immune responses and/or granulomatous inflammation. Mycobacterial and cryptococcal IRD are attributed to a pathological overproduction of Th1 cytokines. Clinicopathological characteristics of IRD associated with viral infections suggest different pathogenic mechanisms. For example, IRD associated with varicella-zoster virus or JC polyomavirus infection correlate with a CD8 T-cell response in the central nervous system. Exacerbations or de novo presentations of hepatitis associated with hepatitis C virus (HCV) infection following ART may also reflect restoration of pathogen-specific immune responses as titers of HCV-reactive antibodies rise in parallel with liver enzymes and plasma markers of T-cell activation. Correlations between immunological parameters assessed in longitudinal sample sets and clinical presentations are required to illuminate the diverse immunological scenarios described collectively as IRD. Here we present salient clinical features and review progress toward understanding their pathogeneses.
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Kim AY, Chung RT. Coinfection with HIV-1 and HCV--a one-two punch. Gastroenterology 2009; 137:795-814. [PMID: 19549523 PMCID: PMC3146750 DOI: 10.1053/j.gastro.2009.06.040] [Citation(s) in RCA: 133] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2009] [Revised: 05/22/2009] [Accepted: 06/13/2009] [Indexed: 12/12/2022]
Abstract
Hepatitis C virus (HCV) infection is a major cause of chronic liver disease, cirrhosis, and death; it is estimated that 180 million persons are infected with HCV worldwide. The consequences of HCV are worse in those who are coinfected with human immunodeficiency virus 1 (HIV-1), which is unfortunately a common scenario because of shared risk factors of the viruses. More studies into effects of HCV/HIV-1 coinfection are needed, but efforts have been hampered by limitations in our understanding of the combined pathogenesis of the 2 viruses. Gaining insight into the mechanisms that underlie the immunopathogenesis of these persistent viral infections could lead to new therapeutic strategies for patients with HCV/HIV-1 coinfection.
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Affiliation(s)
- Arthur Y Kim
- Division of Infectious Diseases and the Ragon Institute of MGH, MIT, and Harvard, Boston, Massachusetts, USA.
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25
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Impaired quality of the hepatitis B virus (HBV)-specific T-cell response in human immunodeficiency virus type 1-HBV coinfection. J Virol 2009; 83:7649-58. [PMID: 19458009 DOI: 10.1128/jvi.00183-09] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Hepatitis B virus (HBV)-specific T cells play a key role both in the control of HBV replication and in the pathogenesis of liver disease. Human immunodeficiency virus type 1 (HIV-1) coinfection and the presence or absence of HBV e (precore) antigen (HBeAg) significantly alter the natural history of chronic HBV infection. We examined the HBV-specific T-cell responses in treatment-naïve HBeAg-positive and HBeAg-negative HIV-1-HBV-coinfected (n = 24) and HBV-monoinfected (n = 39) Asian patients. Peripheral blood was stimulated with an overlapping peptide library for the whole HBV genome, and tumor necrosis factor alpha and gamma interferon cytokine expression in CD8+ T cells was measured by intracellular cytokine staining and flow cytometry. There was no difference in the overall magnitude of the HBV-specific T-cell responses, but the quality of the response was significantly impaired in HIV-1-HBV-coinfected patients compared with monoinfected patients. In coinfected patients, HBV-specific T cells rarely produced more than one cytokine and responded to fewer HBV proteins than in monoinfected patients. Overall, the frequency and quality of the HBV-specific T-cell responses increased with a higher CD4+ T-cell count (P = 0.018 and 0.032, respectively). There was no relationship between circulating HBV-specific T cells and liver damage as measured by activity and fibrosis scores, and the HBV-specific T-cell responses were not significantly different in patients with either HBeAg-positive or HBeAg-negative disease. The quality of the HBV-specific T-cell response is impaired in the setting of HIV-1-HBV coinfection and is related to the CD4+ T-cell count.
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