Major racial and gender differences have been recognized in the natural history of hepatitis C virus (HCV) infection; however, the underlying mechanism for this phenomenon remain poorly understood. In studying the natural history of HCV infection, it has been well-recognized that i) white females have an 8-fold greater chance of spontaneous viral clearance of acute HCV infection; ii) African American (AA) males with genotype 1 HCV infection have higher rates of viral persistence or chronic infection than Caucasian Americans (CA); and iii) these differences are not explained by the baseline viral loads, genotypes, or disease characteristics, but related to the host immune status, in particular T cell responses. In studying the effect of viral infection on T cell functions, we and others have recently found that chronic HCV infection leads to T cell dysfunction mediated through up- regulation of aging markers, including killer cell lectin-like receptor subfamily G member 1 (KLRG1) and dual specific phosphatase 6 (DUSP6), concomitant with a decline of microRNA-181a (miR181) levels in CD4 T cells. These observations suggest that the inability of host to clear virus during chronic infection may be a result of microRNA-mediated impairment of host immunity, and that race/gender influences on the natural history of HCV infection may be due to a difference in virus-induced, miRNA-mediated signaling. Indeed, with increasing age, KLRG1 is up-regulated and leads to inhibition of T cell receptor (TCR) signaling, whereas DUSP6 is increased and leads to recalibration of the TCR activation threshold; miR181 declines to permit translation of a set of genes related to T cell inhibition. However, the mechanisms underlying miR181/KLRG1/DUSP6 expression and regulation of premature T cell aging during HCV infection and their relationships to the gender difference in the natural history of HCV infection remain unclear. We thus hypothesize that virus-induced microRNAs may exhibit a gender difference, which may affect T cell responses that contribute to the natural history of HCV infection. To test this hypothesis, we will carry out the following specific aims: 1) Does HCV induce a different level of miR181, resulting in different T cell responses from male and female HCV-infected or HCV- resolved patients? 2) Are there any differences in miR181 expression in CD4 and CD8 T cells from male and female healthy subjects in response to stimulation by TCR antibodies (anti-CD3/CD28) or HCV antigens? 3) What is the role of HCV-mediated miR181 on host immune responses by gain- or loss-of-function assays, including virus-specific T cell responses? The overall goal of this supplemental proposal is to employ a translational approach to obtain a unified overview on whether HCV may induce different levels of miR181 in T cells from male and female subjects, which may translate into different levels of host T cell responses, and thus contribute to different outcomes of HCV infection.
HCV is characterized by clear race- and gender-related differences in the natural history and outcome of infection. Why this virus is able to persist in the majority of infected individuals, particularly in males versus females, remains unclear, but HCV-induced disruption of host immune responses appears to play a major role. Based on our preliminary studies, we suspect that gender-related difference in microRNA-mediated T cell regulation may explain the altered natural history and outcome of HCV infection. This project will examine whether there is a gender difference in microRNA (miR181 and/or miR155) induction by HCV, and will characterize its role in virus-specific T cell responses. This study will elucidate the gender-related variation of virus-induced microRNAs in the outcome of HCV infection and facilitate effective approaches to improve viral clearance, and thus is significant and timely.
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