Shelterin Dysfunction and p16 INK4a -Mediated Growth Inhibition in HIV-1-Specific CD8 T Cells
Open accessAbstract
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.
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- Authors
- Lichterfeld, M., Cung, T., Seiss, K., Rosenberg, E. S., Pereyra, F., & Yu, X. G.
- Affiliations
- Massachusetts General Hospital (US)
- Harvard University (US)
- Brigham and Women's Hospital (US)
- Venue
- Journal of Virology
- Publisher
- American Society for Microbiology
- Published
- 2012-05-15
- Volume
- 86
- Issue
- 10
- Pages
- 5533-5540
- ISSN
- 0022-538X (ISSN-L)
- 1098-5514
- PMC
- PMC3347267
- OpenAlex
- W2131342326
- Semantic Scholar
- 8bbed68d394b8422792d507609ae6929ede7d216
- Cited by
- 9
- References
- 43
- Citations by year
- 2025: 1 · 2024: 2 · 2022: 2 · 2014: 1 · 2013: 3
- FWCI
- 0.57
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Virology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (R21AI093203, AI074415, P01AI074415, AI078799, R01AI078799, AI093203, P30AI060354)
- Topics
- Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- shelterin, p16INK4a, premature senescence, TRF2, TPP1, 53BP1, telomere maintenance, DNA damage response, anti-PD-1 therapy, HIV disease progression, T cell senescence
- MeSH terms
- Shelterin Complex, Adult, Aged, Female, Humans, Male, Middle Aged, Species Specificity, HIV-1, Down-Regulation, HIV Infections, Up-Regulation, CD8-Positive T-Lymphocytes, Cyclin-Dependent Kinase Inhibitor p16, Telomere-Binding Proteins
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