Expression of inhibitory markers is increased on effector memory T cells during hepatitis C virus/HIV coinfection as compared to hepatitis C virus or HIV monoinfection

摘要

Objective: Hepatitis C virus (HCV)/HIV coinfection is associated with rapid progression of hepatic fibrosis and liver disease. T-cell response has been implicated in the pathophysiological outcome of the disease. Design: This study sought to evaluate the role of memory T-cell exhaustion in enhancing immune dysfunction during coinfection. Methods: Sixty-four patients were included in the study; HCV monoinfected (n=21), HIV monoinfected (n=23), HCV/HIV coinfected (n=20), and healthy controls (n=20). Peripheral blood mononuclear cells (PBMCs) were isolated; immunophenotyped and functional assays were performed. Results: A significant increase in the naive T cells and central memory T cells and a marked reduction in effector memory T cells (TEM) were observed with coinfection as compared to monoinfection. Inhibitory markers programmed death 1 (PD-1) and T-cell immunoglobulin and mucin domain containing molecule 3 (TIM3) were highly upregulated on TEM in coinfection and functionally, these TEM cells displayed lowered proliferation. Increased expression of PD-1 and TIM3 correlated with decreased levels of CD8+CD107a + TEM cells in coinfection. Pro-inflammatory cytokines interferon-g and interleukin-2 (IL-2) secretion by TEM cells were also reduced during chronic viral infection. Secretion of IL-10, a human cytokine synthesis inhibitory factor, was significantly upregulated in CD4 + TEM with HCV/HIV coinfection in comparison to HCV monoinfection. Conclusion: TEM cells play an important role during viral infection and enhanced expression of inhibitory markers is associated with decreased proliferation and cytotoxicity and increased IL-10 production, which was pronounced in HCV/HIV coinfection. Thus, decreased TEM functionality contributes to diminished host immune responses during HCV/HIV coinfection as compared to HCV or HIV monoinfection.