The gastrointestinal (GI) tract is the primary site of HIV replication and CD4+ T cell depletion. HIV induces major alterations at the mucosal sites, which impact their barrier function, permitting transfer of microbial products from the intestinal lumen into the surrounding tissues and into the general circulation. This microbial translocation is a key driver of the chronic immune activation and inflammation (IA/INFL) that are responsible for HIV disease progression. IA/INFL have a tremendous impact on the outcome of HIV infection, and persist even in subjects on antiretroviral therapy (ART), preventing a proper recovery of the CD4+ T cells and being responsible for comorbidities and accelerated aging. Control of chronic IA/INFL is thus one of the major goals both for prevention of HIV-associated comorbidities and for cure strategies. However, even though the impact on the GI tract mucosa appears to be central to HIV pathogenesis, approaches aimed at maintaining or repairing the mucosal barrier are lacking. One of the reasons is that mucosal irritations represented by the continuous transit of food and by digestive secretions are difficult to counterbalance and therefore the lesions persist virtually indefinitely. Our hypothesis is that interventions aimed at repairing the intestinal mucosal damage will be effective in controlling chronic IA/INFL and preventing disease progression, irrespective of the levels of viral replication. We will test three working hypothesis in three different sets of experiments: (i) a therapeutic intervention promoting intestinal health in acutely SIV-infected RMs will lead to a phenotype of viremic controllers of IA/INFL and delayed disease progression; (ii) a therapeutic intervention promoting intestinal healing in acutely SIV-infected RMs on early ART (modeling current guidelines recommending early initiation of ART) will result in a complete control of IA/INFL and in complete immune restoration at the mucosal sites; and (iii) a therapeutic intervention promoting intestinal healing in chronically SIV-infected RMs on prolonged ART (illustrative of the majority of the HIV infected individuals) will result in a complete control of IA/INFL and an improved immune restoration at the mucosal sites. For intestinal healing, we will use an FDA-approved drug (Octreotide, OCT), which (i) reduces intestinal secretions; (ii) reduces/normalizes intestinal peristalsis; (iii) decreases the release of the vasoactive intestinal peptide (VIP), thus inducing descending intestinal relaxation; (iv) reduces GI bleeding. Altogether, these effects have the potential to facilitate intestinal healing. In mice with colitis, somatostatin reduced inflammation and promoted repairs of the tight junctions, confirming the strong scientific premises of this application. Our approach will directly probe the utility of promoting intestinal healing in limiting the deleterious consequences of acute and chronic HIV infection. If successful, our study may lead to a new therapeutic paradigm aimed to preserve gut integrity and avoid disease progression and will have a tremendous impact on HIV infection management.
This application is designed to test the hypothesis that improving gut healing and countering the intestinal dysfunction characteristic to HIV infection will lead acutely SIV-infected RMs to switch to a nonprogressor phenotype, while in animals on ART it will allow control of residual inflammation and immune activation and thus improve the clinical outcome and immune restoration to preinfection levels. We therefore designed a therapeutic intervention that will put the GI tract to rest and accelerate healing of the mucosa. These studies will directly assess the contribution of GI dysfunction to HIV disease progression. If successful, they are highly translational and may inform future therapeutic strategies aimed to preserve gut integrity and avoid disease progression.
