Abstract The advancement of combinational antiretroviral therapy (cART) converts the life of people living with HIV (PLWH) to manageable diseases. However, due to the persistence of viral reservoirs, a cure for HIV remains elusive. That implies we need to eliminate and/or reduce the size of the viral reservoirs to achieve a cure. It has been reported that Neonates/infants whose immune system is dominated by naïve T cells with a limited number of antigen-specific memory T cells have a small HIV reservoir compared to adults. Chronological aging leads to the clonal expansion of effector memory T cells with simultaneous loss of naïve T cells, resulting in a Naïve- memory imbalance. In CNS, with aging, the blood-brain barrier (BBB) leakiness keeps increasing, and chronic activation of microglia/perivascular macrophages occurs. Additionally, aging-associated epigenetic changes in immune cells result in chronic inflammation in older people. How all these factors impact HIV reservoirs in older PLWH remains understudied and has significant implications for developing HIV cure research strategies for aged PLWH. Therefore, this proposal aims to understand how age-associated alterations in composition, epigenetic state, and functionality of immune cells alter the HIV reservoirs using SIV-infected, ART-treated young vs. aged rhesus macaques. We will study the age-associated changes in (1) DNA methylation pattern, (2) SIV integration site, and (3) in composition/functionality of T-cell and monocyte/ macrophages/microglia subsets from PBMC, lymph nodes, rectal tissue, and brain in young vs. aged macaques. Subsequently, we will measure the SIV reservoirs in all these cell types. We anticipate that understanding the aging-associated changes in immune cells at viral reservoir sanctuaries will help to provide a more informed approach to designing HIV cure research interventions for older people living with HIV.