title: Protection of CD4+ T cells from hepatitis C virus infection-associated senescence via ΔNp63-miR-181a-Sirt1 pathway.
abstract: 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.
authors.affiliation: Center for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USA.|Center of Diagnosis and Treatment for Infectious Diseases of Chinese PLA, Tangdu Hospital, Fourth Military Medical University, Xian, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Center for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USA.|Department of Internal Medicine, Division of Infectious Diseases, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USA; and.
authors.forename: Guang Y
authors.initials: GY
authors.lastname: Li
authors.affiliation: Center for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USA.|Department of Internal Medicine, Division of Infectious Diseases, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USA; and.
authors.forename: Jun P
authors.initials: JP
authors.lastname: Ren
authors.affiliation: Center for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USA.|Department of Internal Medicine, Division of Infectious Diseases, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USA; and.
authors.forename: Ling
authors.initials: L
authors.lastname: Wang
authors.affiliation: Center for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USA.|Department of Internal Medicine, Division of Infectious Diseases, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USA; and.
authors.forename: Juan
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Center for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USA.|Department of Internal Medicine, Division of Infectious Diseases, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USA; and.
authors.forename: Shun B
authors.initials: SB
authors.lastname: Ning
authors.affiliation: Center of Diagnosis and Treatment for Infectious Diseases of Chinese PLA, Tangdu Hospital, Fourth Military Medical University, Xian, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Center of Diagnosis and Treatment for Infectious Diseases of Chinese PLA, Tangdu Hospital, Fourth Military Medical University, Xian, China.
authors.forename: Jian Q
authors.initials: JQ
authors.lastname: Lian
authors.affiliation: Center of Diagnosis and Treatment for Infectious Diseases of Chinese PLA, Tangdu Hospital, Fourth Military Medical University, Xian, China.
authors.forename: Chang X
authors.initials: CX
authors.lastname: Huang
authors.affiliation: Center of Diagnosis and Treatment for Infectious Diseases of Chinese PLA, Tangdu Hospital, Fourth Military Medical University, Xian, China; jiazsh@fmmu.edu.cn.
authors.forename: Zhan S
authors.initials: ZS
authors.lastname: Jia
authors.affiliation: Center for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USA.|Department of Internal Medicine, Division of Infectious Diseases, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USA; and.|Hepatitis/AIDS (HCV/HIV) Program, James H. Quillen VA Medical Center, Department of Veterans Affairs, Johnson City, Tennessee, USA.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Moorman
authors.affiliation: Center for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USA; yao@etsu.edu.|Department of Internal Medicine, Division of Infectious Diseases, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USA; and.|Hepatitis/AIDS (HCV/HIV) Program, James H. Quillen VA Medical Center, Department of Veterans Affairs, Johnson City, Tennessee, USA.
authors.forename: Zhi Q
authors.initials: ZQ
authors.lastname: Yao
mesh_terms: D000328:Adult; D000368:Aged; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016022:Case-Control Studies; D016922:Cellular Senescence; D005260:Female; D017930:Genes, Reporter; D019698:Hepatitis C, Chronic / Q000276:immunology*; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D008875:Middle Aged; D015398:Signal Transduction / Q000276:immunology*; D056564:Sirtuin 1 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D059506:Telomere Shortening; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation
chemical_list: D007376:Interleukin-2; C540193:MIrn181 microRNA, human; D035683:MicroRNAs; C115051:TP63 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C447939:SIRT1 protein, human; D056564:Sirtuin 1
keywords:  T cell senescence; Sirtuin 1; hepatitis C; microRNA-181a; transcription factor p63