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

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.