Shelterin Dysfunction and p16 ^INK4a -Mediated Growth Inhibition in HIV-1-Specific CD8 T Cells

Abstract

c 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 p16INK4a , which causes cellular growth inhibition in response to structural DNA damage. Notably, defective shelterin function and upregulation of p16INK4a 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 p16INK4a promote accelerated aging of HIV-1-specific T cells during progressive HIV-1 infection.

T-cell aging in rheumatoid arthritis

“…This compensatory mechanism is defective in RA T cells [14,53]. Insufficient telomeric repair has also been reported for HIV T cells due to abnormalities in the telomeric protection complex of the shelterin proteins, thereby leaving chromosomal ends exposed [70] * .…”

PD-1 coinhibitory signals: The link between pathogenesis and protection

“…The telomere length in HIV-specific CD8 T cells approaches the Hayflick limit for terminal senescence during progressive HIV infection [22, 55, 68]. The shortened telomeres observed in HIV-specific CD8 T cells correlated with reduced expression of proteins of the shelterin complex and disruption of shelterin complex formation [69]. The shelterin complex is a group of nucleoproteins found at the terminal ends of chromosomal DNA whose function is to protect telomeric DNA and regulate telomerase activity [70, 71].…”

“…This lead to improved clinical outcomes in SIV infected rhesus macaques treated with PD-1 blocking antibody [74]. These data suggest that HIV-specific CD8 T cells with shortened telomeres are not in a state of irreversible DNA repair and that recovery of telomere length may contribute to the rescue of cytotoxic effector functions [69]. However, Lichterfeld et al also found that despite an observed increase in telomere length, PD-1 blocking antibody treatment did not result in stabilization to normal levels in the protein expression of the components of the shelterin complex that protect exposed telomere ends and which could influence long term survival [69].…”

Accelerated Neuroimmune Dysfunction in Aged HIV-1-Infected Humanized Mice

“…TPP1, a nucleoprotein pivotal for maintaining telomere integrity and homeostasis, showed elevated levels in our aged, infected samples. However, TPP1’s function in chronically HIV-infected patients remains unclear [ 54 , 55 ]. We noted an upregulation of the genomic instability marker, zinc metalloproteinase ZMPSTE24, which has been associated with increased levels of inflammation and an increase in progerin mRNA, both recognized as indicators of aging [ 56 ].…”