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 1 T cells positively correlated with a clinical parameter of liver disease progression. HCV-specific CD8 1 T cells showed greater frequencies of Tim-3/PD-1 co-expression than HIV-specific CD8 1 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 1 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.

Antigen-Independent Induction of Tim-3 Expression on Human T Cells by the Common γ-Chain Cytokines IL-2, IL-7, IL-15, and IL-21 Is Associated with Proliferation and Is Dependent on the Phosphoinositide 3-Kinase Pathway

“…Increased frequency of Tim-3 + T cells is reported in tuberculosis (8). We and other investigators subsequently showed that the chronic virus infections HIV-1 (9) and hepatitis C virus (10,11) are also associated with upregulation of Tim-3 on T cells. In addition, elevated expression of Tim-3 on virus-specific T cells correlated with increased viral load and disease progression (8)(9)(10)(11).…”

“…We and other investigators subsequently showed that the chronic virus infections HIV-1 (9) and hepatitis C virus (10,11) are also associated with upregulation of Tim-3 on T cells. In addition, elevated expression of Tim-3 on virus-specific T cells correlated with increased viral load and disease progression (8)(9)(10)(11). Subsequent studies showed that Tim-3 expression is also upregulated on tumor-infiltrating T cells, thus providing an additional mechanism of tumor escape from the immune response (12).…”

CXCL10/CXCR3-Dependent Mobilization of Herpes Simplex Virus-Specific CD8 + T EM and CD8 + T RM Cells within Infected Tissues Allows Efficient Protection against Recurrent Herpesvirus Infection and Disease

“…The amount of viral Ag produced in the latently infected TG of mice following UV-B reactivation is quite low, less than 1 positive neuron/TG (66)(67)(68)(69). Thus, it is likely that the CXCL10/CXCR3 chemokine pathway inhibits exhaustion of CD8 ϩ T cells in TG through mechanisms other than Ag persistence, as we previously discussed (70).…”

“…Antibodies targeting the PD-1/PD-L1 (programmed death ligand 1) immune checkpoint have recently shown remarkable clinical safety and efficacy in other systems (76)(77)(78). The current largely accepted paradigm is that exhaustion of T cells requires persistent exposure to Ag (66)(67)(68)(69). Elucidating the mechanisms by which the CXCL10/CXCR3 pathway might be preventing CD8 ϩ T cell exhaustion remains to be determined.…”

Rapid diagnostic HCV antibody assays

“…This issue is of particular concern because the prevalence of HCV infection among HIV-positive persons is high (24%) and, conversely, 81% of HIV-positive persons with a history of IDU are anti-HCV-positive [13]. HIV-HCV-coinfected persons are at a greater risk of progressing to an AIDS-defining event or death than those who are HIV monoinfected [29], and progress to end-stage liver disease in less than half the time of HCV-monoinfected persons [30,31].…”