Hepatitis C virus–induced reduction in miR‐181a impairs CD4+ T‐cell responses through overexpression of DUSP6

T cells play a crucial role in viral clearance or persistence; however, the precise mechanisms that control their responses during viral infection remain incompletely understood. MicroRNA (miR) has been implicated as a key regulator controlling diverse biological processes through posttranscriptional repression. Here, we demonstrate that hepatitis C virus (HCV)–mediated decline of miR‐181a expression impairs CD4+ T‐cell responses through overexpression of dual specific phosphatase 6 (DUSP6). Specifically, a significant decline of miR‐181a expression along with overexpression of DUSP6 was observed in CD4+ T cells from chronically HCV‐infected individuals compared to healthy subjects, and the levels of miR‐181a loss were found to be negatively associated with the levels of DUSP6 overexpression in these cells. Importantly, reconstitution of miR‐181a or blockade of DUSP6 expression in CD4+ T cells led to improved T‐cell responses including enhanced CD25 and CD69 expression, increased interleukin‐2 expression, and improved proliferation of CD4+ T cells derived from chronically HCV‐infected individuals. Conclusion: Since a decline of miR‐181a concomitant with DUSP6 overexpression is the signature marker for age‐associated T‐cell senescence, these findings provide novel mechanistic insights into HCV‐mediated premature T‐cell aging through miR‐181a‐regulated DUSP6 signaling and reveal new targets for therapeutic rejuvenation of impaired T‐cell responses during chronic viral infection. (Hepatology 2015;61:1163–1173)