This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. HIV and SIV replication has been highlighted to predominantly occur in the GI tract contributing to most of the viremia detected in blood. As a consequence of such localized active infection, HIV infected patients experiment malabsorption early on as well as signs of GI inflammation leading to increased GI permeability and even bacterial translocation. FXR agonists have been shown to favorably impact maintenance of intestinal mucosal barrier integrity, inflammatory cell infiltration and villus architecture in rodent models of non-HIV enteropathy. Our initial hypothesis suggests that the treatment of an SIV-infected animal with an FXR agonist will aid in the restoration and repair of the gut tissue and subsequently lead to a decrease in microbial translocation and associated effects. As an extension of this hypothesis, we propose to explore a treatment with an FXR agonist on the course of SIV infection. We hypothesize that the chronic treatment with an FXR agonist will benefit the gut tissue in chronic SIV infection leading to improvement in markers of enteropathy, decreased evidence of microbial translocation, decreased systemic immune activation and/or increased reconstitution of gastrointestinal associated lymphoid tissue. For this pilot proposal, a set of 5 rhesus macaque chronically infected with SIV are being treated daily with the FXR agonist via oral administration. Plasma biomarkers, viral loads and immune responses are being monitored as well as the GI permeability and tissue architecture, to document the potential clinical benefit of such therapy in chronic lentivirus infection.
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