There are now many FDA approved antiretroviral (ART) drugs for the treatment of HIV infection that are well tolerated, capable of durably suppressing HIV RNA, improving CD4+ cell counts and reducing AIDS-defining events. However, there are residual challenges in defining optimal ART considering it is life-long treatment in an aging population. This has motivated research to explore the effects of different regimens on non-virologic parameters such as host genetics, the aging process and age-related co-morbidities. Telomeres, nucleoproteins containing TTAGGG repeats that protect the ends of chromosomes from degradation, undergo progressive shortening after each cellular division. When telomeres reach a critical length, affected cells become senescent or dysfunctional. Telomere length (TL) is maintained by the enzyme telomerase. Telomerase is a ribonucleoprotein enzyme complex containing a critical telomerase reverse transcriptase (TERT) subunit that adds nucleotides to telomeres, thereby prolonging the life span of a cell and maintaining replicative capacity. TL decreases with age and exposures causing chronic inflammation and oxidative stress accelerate this process. Several studies have linked shorter TL to increased risk of age-associated diseases. HIV infection itself, high replicating virus, poor immunologic recovery during ART and levels of certain inflammatory biomarkers have been associated with TL shortening. In vitro data suggests that virtually all of the nucleoside reverse transcriptase inhibitors (NRTIs) promote aging as measured by TL and reduced TERT activity. Ex vivo, shorter TL and decreased telomerase activity has been observed in PBMCs from HIV-infected individuals receiving NRTIs compared to HIV uninfected persons and those on NRTI-sparing ART. Tenofovir (TFV) – the most widely used NRTI in clinical practice – has the greatest negative impact on TL and telomerase activity in vitro and the only clinical study was not large enough to evaluate specific NRTIs. The second most used NRTI, abacavir, has also been shown to accelerate shortening of TL and inhibit telomerase in vitro, but at higher concentrations than TFV. There have been no clinical studies evaluating TL and associations with age-related diseases among HIV-infected populations. Given current recommendations advocating ART initiation regardless of CD4+ cells counts or HIV RNA levels and the rising representation of individuals over 45 years old in the HIV-infected population, we must gain a better understanding of how contemporary ART impacts molecular aging, and explore whether this interacts with known disease phenotypes of aging. Our research aligns well with the NIH OAR high priority topic of “HIV-associated comorbidities, coinfections, and complications including: addressing the impact of HIV-associated comorbidities, including tuberculosis, malignancies; cardiovascular, neurological, and metabolic complications; and premature aging associated with long-term HIV disease and antiretroviral therapy.” We have received institutional support from a pilot grant for $10,000 to begin this work and get preliminary data, however, funds through this FOA would allow us to expand this further and examine associations between TL, mechanisms, and age related disease endpoints in the entire cohort.
|Effective start/end date||12/1/16 → 11/30/18|
- Brigham and Women's Hospital (1165293//5UM1AI068636-11)
- National Institute of Allergy and Infectious Diseases (1165293//5UM1AI068636-11)
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