Age-Associated Expansion of HIV/SIV Reservoirs in People With HIV and SIV-Infected Macaques

With the advancement of combination antiretroviral therapy (ART), over 50% of people with HIV (PWH) in the United States are now over the age of 50. A hallmark of the aging immune system is a progressive dysfunction of both the innate and adaptive immune responses, often characterized by clonal expansion of memory T cells. However, the impact of age-related immune dysfunction on HIV/SIV reservoir dynamics remains understudied. We hypothesized that age-associated clonal expansion of memory T cells contributes to the increase of the HIV reservoirs in older PWH (OPWH). In this retrospective study, we utilized archived peripheral blood mononuclear cells (PBMCs) from young and older PWH with suppressed plasma viremia for at least 5 years and quantified both intact and total HIV proviral DNA from CD4+ T cells. Alongside the human study, we also analyzed samples from SIV-infected, ART-suppressed young and aged rhesus macaques, quantifying intact and total proviruses in CD4+ T cells. We observed a significantly higher level of intact and total proviral DNA in older compared to younger PWH. The frequency of intact provirus was positively correlated with activated CD4+ and CD8+ T cells. Consistently, in the non-human primate model, aged macaques exhibited significantly higher levels of intact and total SIV proviruses in CD4+ T cells than their younger counterparts. Collectively, these findings suggest that the HIV/SIV reservoir expands with age, potentially driven by immune activation. Future studies are warranted to elucidate the mechanisms underlying reservoir expansion in the aging population.