Hepatology 2015-04-01

Hepatitis C virus-induced reduction in miR-181a impairs CD4(+) T-cell responses through overexpression of DUSP6.

Guang Y Li, Yun Zhou, Ruo S Ying, Lei Shi, Yong Q Cheng, Jun P Ren, Jeddidiah W D Griffin, Zhan S Jia, Chuan F Li, Jonathan P Moorman, Zhi Q Yao

Index: Hepatology 61(4) , 1163-73, (2015)

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Abstract

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.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.© 2014 by the American Association for the Study of Liver Diseases.