title: 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.
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.
authors.affiliation: Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
authors.forename: Bahareh
authors.initials: B
authors.lastname: Vali
authors.forename: R Brad
authors.initials: RB
authors.lastname: Jones
authors.forename: Ali
authors.initials: A
authors.lastname: Sakhdari
authors.forename: Prameet M
authors.initials: PM
authors.lastname: Sheth
authors.forename: Kiera
authors.initials: K
authors.lastname: Clayton
authors.forename: Feng-Yun
authors.initials: FY
authors.lastname: Yue
authors.forename: Gabor
authors.initials: G
authors.lastname: Gyenes
authors.forename: David
authors.initials: D
authors.lastname: Wong
authors.forename: Marina B
authors.initials: MB
authors.lastname: Klein
authors.forename: Sahar
authors.initials: S
authors.lastname: Saeed
authors.forename: Erika
authors.initials: E
authors.lastname: Benko
authors.forename: Colin
authors.initials: C
authors.lastname: Kovacs
authors.forename: Rupert
authors.initials: R
authors.lastname: Kaul
authors.forename: Mario A
authors.initials: MA
authors.lastname: Ostrowski
mesh_terms: D019138:Antibodies, Blocking / Q000494:pharmacology; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000956:Antigens, Viral / Q000276:immunology; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D049109:Cell Proliferation / Q000187:drug effects; D002469:Cell Separation; D002478:Cells, Cultured; D018450:Disease Progression; D005260:Female; D005434:Flow Cytometry; D015658:HIV Infections / Q000150:complications / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D015497:HIV-1 / Q000276:immunology* / Q000472:pathogenicity; D015234:HLA-A Antigens / Q000276:immunology / Q000378:metabolism; D015789:HLA-A2 Antigen; D016174:Hepacivirus / Q000276:immunology* / Q000472:pathogenicity; D000072597:Hepatitis A Virus Cellular Receptor 2; D006526:Hepatitis C / Q000150:complications / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D008099:Liver / Q000276:immunology / Q000473:pathology / Q000821:virology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D061026:Programmed Cell Death 1 Receptor
chemical_list: D019138:Antibodies, Blocking; D015703:Antigens, CD; D000956:Antigens, Viral; D051017:Apoptosis Regulatory Proteins; C448908:HAVCR2 protein, human; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D000072597:Hepatitis A Virus Cellular Receptor 2; D008565:Membrane Proteins; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor