Protection of CD4+ T Cells From Hepatitis C Virus Infection-Associated Senescence via ΔNp63-miR-181a-Sirt1 Pathway

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T cell dysfunction has a crucial role in establishing and maintaining viral persistence. We have previously shown a decline in miR‐181a, which regulates CD4+ T cell responses via DUSP6 overexpression, in individuals with hepatitis C virus (HCV) infection. Here, we describe accelerated T cell senescence in HCV‐infected individuals compared with age‐ and sex‐matched healthy subjects. Mechanistic studies revealed that up‐regulation of transcription factor ΔNp63 led to the decline of miR‐181a expression, resulting in an overexpression of the antiaging protein Sirt1, in CD4+ T cells from HCV‐infected individuals. Either reconstituting miR‐181a or silencing ΔNp63 or Sirt1 expression in CD4+ T cells led to accelerated T cell senescence, as evidenced by an increased senescence‐associated β‐galactosidase (SA‐β‐gal) expression, shortened telomere length, and decreased EdU incorporation; this suggests that HCV‐induced T cell senescence is counterregulated by the ΔNp63–miR‐181a–Sirt1 pathway. An increase of IL‐2 production was observed in these senescent CD4+ T cells and was driven by a markedly reduced frequency of Foxp3+ regulatory T (Treg) cells and increased number of Foxp3− effector T (Teff) cells upon manipulating the ΔNp63–miR‐181a–Sirt1 pathway. In conclusion, these findings provide novel mechanistic insights into how HCV uses cellular senescent pathways to regulate T cell functions, revealing new targets for rejuvenating impaired T cell responses during chronic viral infection.