Persons living with HIV (PLWH) have an increased risk of developing AIDS-defining and non-AIDS-defining cancer. This is a significant healthcare and economical concern as this population is surviving longer and living fuller and productive lives owing to the advent of antiretroviral therapy (ART). Several parameters are associated with this increased incidence in cancer, but two factors that are consistent with cancer development, in general, are the increasing age of PLWH, which implies an interplay between aging and HIV infection that results in an increased incidence of cancer. Aging is well known to be a risk factor for developing non-AIDS-defining cancer, however; aged PLWH are 3 times more likely to develop non-AIDSdefining cancer than the comparable normal immunocompetent aged population. Thus, viral, cellular and molecular factors that change over time, due to aging and HIV-infection must intersect to accelerate the processes that make this population more at risk to develop cancer. Aspects of this can be studied longitudinally in PLWH, but this approach has shortcomings and is dependent upon the enrollment of patients, who may drop out due to relocation or disinterest. An alternative approach is to investigate an animal model that closely parallels most, if not all, aspects of HIV pathogenesis. Here, we use the widely accepted simian immunodeficiency virus (SIV) infected nonhuman primate (NHP) model that recapitulates multiple aspects of HIV pathogenesis, including development of AIDS-related malignancies and virusassociated neurological complications or neuro-AIDS. This NHP model utilizes purpose-bred Indian-origin rhesus macaques (RM) that approximates HIV infection and can be surgically and immunologically manipulated to investigate the alterations that occur and lead to cancer development and progression. Our studies will be performed on two cohorts of SIV-infected RM; one aged (n=8 RM, >20 years old) and one adult (n=10 RM, 6-10 years old). This is a longitudinal-based study where we will have collected pre- and post-SIV infection samples, and will continue to collect and characterize the host immune response by multi-color flow cytometry (FCM) and define the molecular signatures in normal adjacent tissue and cancer tissue by single-cell (sc) RNA sequencing (RNA-seq), total RNA-seq and/or Nanostring analysis. Combining these in vivo and in vitro experiments to address cancer development and progression in a controlled research environment where subject conditions are routinely monitored and maintained daily on ART, will enable our team and others to dissect how alterations in the host impact disease in susceptible populations.