Epigenetic age acceleration and differences among immune cell populations in people with and without HIV - Project Summary / Abstract With effects on multiple cellular mechanisms of aging – including systemic inflammation, cellular senescence, and DNA damage – HIV infection is a recognized biological model of age acceleration. Indeed, people living with HIV (PWH) experience higher risk and earlier onset of a number of aging-related conditions, including cardiovascular disease, frailty, and cognitive and physical function decline. Addressing the excess burden of comorbidities, including geriatric syndromes, experienced by PWH is an NIH and public health priority. Objective measures of accelerated aging are urgently needed for mechanistic, clinical, and interventional investigations to improve aging-related outcomes of PWH. Epigenetic age acceleration (EAA) has been proposed as one such measure, which is based on calculating differences between chronological age versus biological age predicted from DNA methylation patterns. Previous studies have shown, using whole-blood samples, that the epigenomes of PWH on antiretroviral therapy look 5 years older than expected based on their chronological age. Expansion of the use of EAA into studies of aging biology and interventions has been limited due to the high cost of the assay and our incomplete understanding of differences in EAA among cell types, including immune cell types most affected by HIV infection. The overall objective of this study is to examine differences in EAA across immunologic cell profiles in people with and without HIV. Using cryopreserved PBMC samples and existing detailed cellular and clinical outcome data of younger (n=35; 30-39 years) and older (n=105; ≥50 years) individuals with and without HIV, Aim 1 of the study will examine whether bulk-PBMC EAA measures predict changes in clinical (frailty, cognitive performance, comorbidity) and immunologic aging profiles (CD4 and CD8 subpopulation measures of activation, senescence, and exhaustion) in people with and without HIV using a novel, cost-effective DNA methylation assay. Aim 2 will examine effects of HIV infection and aging on EAA measures of sorted immune cell populations, namely naïve and memory T cell subsets, B cells, monocytes, and NK cells. Our overarching hypothesis is that HIV infection will be associated with increased and more varied EAA among immune cell populations and that measures of EAA will predict accelerated measures of adaptive immune senescence. Results of this study will provide critical evaluation of epigenetic clock performance in PWH and will provide novel insights in the cellular populations driving accelerated aging outcomes in this population. Led by a multidisciplinary team of experts in clinical epidemiology of HIV and aging, evolutionary biology and genomic science, and the immunology of HIV, our team will leverage powerful genomic, HIV, immunologic institutional research resources for the efficient and successful execution of this 2-year, innovative R21 study of epigenetic age acceleration, immunology, and HIV.
