title: Shelterin dysfunction and p16(INK4a)-mediated growth inhibition in HIV-1-specific CD8 T cells.
abstract: HIV-1-specific cytotoxic T cell responses are expanded during advanced HIV-1 infection but seem unable to effectively protect the host against disease progression. These cells are able to produce gamma interferon and remain metabolically active but have defective proliferative activities, shortened telomeric DNA, and other signs of accelerated aging. To investigate the molecular mechanisms underlying the premature senescence of HIV-1-specific T cells, we focused here on the expression and function of a group of six nucleoproteins that are responsible for protecting and maintaining the structural integrity of telomeric DNA and are commonly referred to as "shelterin." We show that in progressive HIV-1 infection, the two major shelterin components TRF2 and TPP1 are selectively reduced in HIV-1-specific CD8 T cells, but not in T cells recognizing alternative viral species. This coincided with increased recruitment of 53BP1, a prominent DNA damage response factor, to telomeric DNA sites and was associated with elevated expression of the tumor suppressor p16(INK4a), which causes cellular growth inhibition in response to structural DNA damage. Notably, defective shelterin function and upregulation of p16(INK4a) remained unaffected by experimental blockade of PD-1, indicating a possibly irreversible structural defect in HIV-1-specific CD8 T cells in progressors that cannot be overcome by manipulation of inhibitory cell-signaling pathways. These data suggest that shelterin dysfunction and ensuing upregulation of the tumor suppressor p16(INK4a) promote accelerated aging of HIV-1-specific T cells during progressive HIV-1 infection.
authors.affiliation: Infectious Disease Division, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Mathias
authors.initials: M
authors.lastname: Lichterfeld
authors.forename: Thai
authors.initials: T
authors.lastname: Cung
authors.forename: Katherine
authors.initials: K
authors.lastname: Seiss
authors.forename: Eric S
authors.initials: ES
authors.lastname: Rosenberg
authors.forename: Florencia
authors.initials: F
authors.lastname: Pereyra
authors.forename: Xu G
authors.initials: XG
authors.lastname: Yu
mesh_terms: D000328:Adult; D000368:Aged; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism / Q000821:virology*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D005260:Female; D015658:HIV Infections / Q000821:virology*; D015497:HIV-1 / Q000254:growth & development* / Q000502:physiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D000089804:Shelterin Complex; D013045:Species Specificity; D034501:Telomere-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C495876:ACD protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D000089804:Shelterin Complex; D034501:Telomere-Binding Proteins