title: Hepatitis C virus-induced reduction in miR-181a impairs CD4(+) T-cell responses through overexpression of DUSP6.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Center for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN.
authors.forename: Guang Y
authors.initials: GY
authors.lastname: Li
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhou
authors.forename: Ruo S
authors.initials: RS
authors.lastname: Ying
authors.forename: Lei
authors.initials: L
authors.lastname: Shi
authors.forename: Yong Q
authors.initials: YQ
authors.lastname: Cheng
authors.forename: Jun P
authors.initials: JP
authors.lastname: Ren
authors.forename: Jeddidiah W D
authors.initials: JW
authors.lastname: Griffin
authors.forename: Zhan S
authors.initials: ZS
authors.lastname: Jia
authors.forename: Chuan F
authors.initials: CF
authors.lastname: Li
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Moorman
authors.forename: Zhi Q
authors.initials: ZQ
authors.lastname: Yao
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000502:physiology*; D002478:Cells, Cultured; D054642:Dual Specificity Phosphatase 6 / Q000096:biosynthesis*; D016174:Hepacivirus / Q000502:physiology*; D006801:Humans; D035683:MicroRNAs / Q000502:physiology*
chemical_list: C540193:MIrn181 microRNA, human; D035683:MicroRNAs; C517035:DUSP6 protein, human; D054642:Dual Specificity Phosphatase 6