PROJECT SUMMARY/ABSTRACT COVID-19 vaccination reduces the risk of SARS-CoV-2 infection and severe disease, but almost half of hospitalized breakthrough cases are in immunocompromised individuals. HIV infection is an independent risk factor for severe COVID-19, hospitalization, and mortality. Immunocompromised individuals are more likely to have prolonged SARS-CoV-2 infection and viral shedding, increasing the risk of viral transmission and allowing for rapid evolution of more virulent strains. Therefore, investigating SARS-CoV-2 pathogenesis in the context of immunosuppression is urgently needed to reveal factors driving severe COVID-19. SARS-CoV-2 lung pathogenesis is characterized by infiltration of innate and adaptive immune cells into the lung and induction of an inflammatory immune response. Similar mechanisms of inflammation and immune dysfunction during HIV infection contribute to systemic HIV pathogenesis and lung pathology. Therefore, dysregulation of immune responses during HIV infection could induce severe disease outcomes during SARS-CoV-2 coinfection. SARS- CoV-2 replication occurs in both respiratory and gastrointestinal mucosal sites and enteric symptoms are associated with COVID-19. There is a defined link between gastrointestinal microbial dysbiosis with accelerated HIV disease progression and an emerging role of lung and intestinal microbial dysbiosis with severe COVID-19. Given that the microbiome plays an important role in maintaining mucosal function and homeostasis, shifts in microbial communities due to HIV infection could contribute to inflammation and immune activation that would drive exacerbated SARS-CoV-2 pathogenesis. Here, we will test the hypothesis that increased immune dysfunction and exhaustion, inflammation, and microbial dysbiosis during HIV infection promote enhanced SARS-CoV-2 lung pathogenesis. We will leverage the pigtail macaque simian immunodeficiency virus (SIV) model of rapid HIV/AIDS and will test this hypothesis during a state of inflammatory untreated SIV infection and during primary and secondary SARS-CoV-2 viral challenges. We will evaluate the roles of SIV-induced immunosuppression and altered alveolar macrophage and neutrophil function on SARS-CoV-2 pathogenesis and pulmonary pathology. We will determine whether HIV infection causes gastrointestinal tract and lung microbial dysbiosis and its association with SARS-CoV-2 disease severity. Lastly, we will determine whether increased immune exhaustion during HIV infection promotes deficits in the generation of primary anti-viral SARS- CoV-2 responses that impairs protection from heterologous SAR-CoV-2 re-challenge. These studies will contribute to our understanding of how normal immunity drives SARS-CoV-2 lung pathophysiology and will dissect how perturbations of immune responses during HIV infection contribute to enhanced disease.