Summary While COVID-19 continues to be a health challenge, very little is known about how COVID-19 affects people living with HIV (PLHIV). Based on the most recent reports originating from CDC and WHO, however, it appears that people with HIV may have a 30% greater likelihood of developing severe COVID-19 disease when infected with SARS-CoV-2. We will leverage the established rhesus macaque models of SARS-CoV-2 infection resulting in COVID-19 and SIV infection to characterize the effects of underlying SIV infection on the manifestation of both acute and post-acute COVID-19 sequelae. Our group was amongst few that established the rhesus macaque models of COVID-19 infection early on during the pandemic. Our model has been utilized to both study the immunological mechanisms of protection from SARS-CoV-2 infection, as well as for accelerated development of vaccine and therapeutics against COVID-19. Here we propose to couple this model with the long-standing, highly validated, pathogenic AIDS NHP model in SIV infected rhesus macaques to study a central hypothesis that underlying SIV infection and the resulting immunodeficiency/immune activation promotes the progression of a more severe COVID-19 presentation due to SARS-CoV-2 infection. As corollary, we hypothesize that ART does not completely suppress the ill effects of chronic immune activation due to SIV, it will not completely prevent the progression of severe COVID-19 due to SARS-CoV-2 infection in the macaque model. We have the experience in infecting rhesus macaques with SIV and treating these animals with ART to suppress viral replication and study immune mechanisms. By profiling the differences in dynamics of viral titers, induced tissue pathology, and underlying immunological perturbations, we will provide definitive knowledge in whether SIV infected rhesus macaques exhibit higher susceptibility to severe COVID-19. Furthermore, our studies will also be able to hint at the specific mechanisms which result in this susceptibility. Delineating these comorbid immunological factors driving susceptibility will enable better clinical monitoring and informed decisions for patient care. Mechanistic insights developed by this study is also imperative for the development of host-directed immunotherapeutic interventions for combating COVID-19 in PLHIV.