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Abstract
Although extensive studies have demonstrated the functional impairment of antigen-specific CD4+ and CD8+ T-cells during chronic hepatitis C virus (HCV) infection, the functional status of global CD4+ and CD8+ T-cells remains unclear. In this report, we recruited 42 long-term (~20 years) treatment-naïve chronic HCV (CHC) patients and 15 healthy donors (HDs) to investigate differences in global CD4+ and CD8+ T-cells function. We show that CD4+ and CD8+ T-cells from CHC patients underwent increased apoptosis after TCR stimulation. Furthermore, IFN-γ, IL-9 and IP-10 were elevated in CHC patients’ plasma and promoted activation-induced T-cells death. Global CD4+ and CD8+ T-cells also showed unique transcriptional profiles in the expression of apoptosis-related genes. We identified BCL2, PMAIP1, and CASP1 in CD4+ T-cells and IER3 and BCL2A1 in CD8+ T-cells from CHC patients as HCV-specific gene signatures. Importantly, the gene expression patterns of CD4+ and CD8+ T-cells from CHC patients differ from those in CD4+ and CD8+ T-cells from human immunodeficiency virus type 1 (HIV-1) or hepatitis B virus (HBV) infected individuals. Our results indicate that chronic HCV infection causes a systemic change in cytokine levels that primes T-cells for activation-induced apoptosis. Furthermore, HCV infection programs unique apoptosis-related gene expression profiles in CD4+ and CD8+ T-cells, leading to their enhanced activation-induced apoptosis. These results provide novel insights to the pathogenesis of chronic HCV infection.
Highlights
170 million people are chronically infected with hepatitis C virus (HCV) [1,2]
Alanine transaminase (ALT) and total bilirubin (TBIL) values were significantly higher in all 3 groups of chronic HCV (CHC) patients than in healthy donors (HDs) (Figure 1B)
The direct bilirubin (DBIL) values in HCV-l and HCV-h patients were within the normal range, they were significantly higher than those in HDs (Figure 1B)
Summary
170 million people are chronically infected with hepatitis C virus (HCV) [1,2]. The functional exhaustion of HCV-specific T-cells contributes to failed viral clearance in chronically infected patients [3,4,5]. HCV-specific CD8+ T-cells exhibit various degrees of functional impairment, including impaired proliferation, reduced effector cytokine production, and enhanced apoptosis [6,7,8]; the mechanisms underlying these changes are incompletely understood. Deregulated expression of inhibitory receptors on HCV-specific CD8+ T-cells, increased Treg numbers, and enhanced cytokine levels impact the function of antigen-specific T-cells during chronic HCV infection [3,4]. HCV infection on the function of global CD4+ and CD8+ T lymphocytes remains poorly understood. Addressing this issue will elucidate mechanisms by which the host environment impacts antigen-specific T-cells during chronic HCV infection
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