Extracellular adenosine (ADO) is a potent immunoregulatory nucleoside that limits tissue damage due to inflammation. ADO is produced by the action of cell surface ectoenzymes (CD39/CD73) that metabolize adenosine triphosphate (ATP) or nicotinamide adenine dinucleotide (NAD+) into adenosine monophosphate (AMP) and then into ADO. Our NHP studies showed that, upon SIV infection, the levels of ADO in the gut tissues are lower in models of pathogenic infection (pigtailed macaques, PTMs; which develops severe gut dysfunction and systemic INFL upon the SIV infection) than in models of nonpathogenic infection (African green monkeys, AGMs; which maintain an intact gut barrier and baseline levels of IA/INFL upon SIV infection). The different CD39/CD73 expression on mucosal Tregs and contrasting ADO levels in these species with divergent inflammatory responses to SIV support a key role of ADO in controlling IA/INFL in nonpathogenic SIV infections. Changes in ADO levels predominately occurred in the gut, suggesting that the ADO pathway may be involved in sparing the AGMs from developing SIV-related gut dysfunction. These findings strongly support a significant involvement of the ADO pathway in the pathogenesis of SIV/HIV related gut dysfunction and indicate that more focused studies aimed to harness the ADO pathway at mucosal sites of viral replication are needed. In this project, we will directly test the hypothesis that the ADO signaling pathway plays a pivotal role in modulating the inflammatory gut mucosal environment after SIV/HIV infection, through an intervention aimed at increasing ADO production in a model of pathogenic SIV infection. We will administer the HIF-1α prolyl-hydroxylase inhibitor Roxadustat to chronically SIV-infected NHPs and assess its impact on the gut integrity and on key parameters of SIV pathogenesis. Our objectives are to assess the impact of increasing ADO signaling on (i) alleviating gut dysfunction and systemic INFL and (ii) virus reservoirs. These innovative experiments will directly probe a new regulatory inflammatory pathway, enabling us to decipher the mechanisms responsible for the HIV/SIV-related gut dysfunction. As such, our studies will inform future therapeutic strategies aimed at preservation of gut integrity and control of residual IA/INFL that are the root causes of multiple comorbidities. Finally, if successful, our experiments may be directly translated as a new therapeutic strategy to alleviate SIV/HIV-related gut dysfunction.