Gender difference in miRNA-mediated T cell aging during viral infection

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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.