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

• Published in: European journal of immunology Vol. 40; no. 9; pp. 2493 - 2505
• Main Authors: Vali, Bahareh, Jones, R. Brad, Sakhdari, Ali, Sheth, Prameet M, Clayton, Kiera, Yue, Feng-Yun, Gyenes, Gabor, Wong, David, Klein, Marina B, Saeed, Sahar, Benko, Erika, Kovacs, Colin, Kaul, Rupert, Ostrowski, Mario A
• Format: Journal Article
• Language: English
• Published: Weinheim Wiley-VCH Verlag 01.09.2010; WILEY‐VCH Verlag; Wiley Subscription Services, Inc
• Subjects: Antibodies, Blocking - pharmacology; Antigens, CD - genetics; Antigens, CD - immunology; Antigens, CD - metabolism; Antigens, Viral - immunology; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - immunology; Apoptosis Regulatory Proteins - metabolism; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; CD8-Positive T-Lymphocytes - pathology; CD8-Positive T-Lymphocytes - virology; Cell Proliferation - drug effects; Cell Separation; Cells, Cultured; Disease Progression; Female; Flow Cytometry; Hepacivirus - immunology; Hepacivirus - pathogenicity; Hepatitis A Virus Cellular Receptor 2; Hepatitis C; Hepatitis C - complications; Hepatitis C - immunology; Hepatitis C - pathology; Hepatitis C - physiopathology; Hepatitis C virus; HIV; HIV Infections - complications; HIV Infections - immunology; HIV Infections - pathology; HIV Infections - physiopathology; HIV-1 - immunology; HIV-1 - pathogenicity; HLA-A Antigens - immunology; HLA-A Antigens - metabolism; HLA-A2 Antigen; Human immunodeficiency virus; Humans; Infections; Lentivirus; Liver - immunology; Liver - pathology; Liver - virology; Liver diseases; Lymphocytes; Male; Membrane Proteins - genetics; Membrane Proteins - immunology; Membrane Proteins - metabolism; Programmed Cell Death 1 Receptor; Retroviridae; T‐cell exhaustion
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.201040340

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.