Assessing the Role of GI Tract Dysfunction to HIV/SIV Disease Progression

Alterations of the mucosal barrier followed by microbial translocation are common in pathogenic HIV/SIV infections. HIV-associated enteropathy was observed early in the pandemic, but a direct causative relationship between HIV/SIV disease progression and gastrointestinal (GI) tract dysfunction is still to be proven. The triggers of HIV/SIV– related gut dysfunction are poorly understood too. In pathogenic HIV/SIV infections, intestinal dysfunction occurs following initial virus replication, CD4+ T cell depletion, epithelial damage and microbial dysbiosis, and these phenomena cannot be dissociated, being difficult to dissect their relative contribution to disease progression. Conversely, African green monkeys (AGMs), which maintain mucosal integrity throughout infection in spite of high SIV loads, are ideal models to dissect the relative contribution of different potential mechanisms of the mucosal dysfunction. During the previous funding period, we demonstrated that, in SIV-infected AGMs (a) Experimental induced systemic T-cell activation in the absence of mucosal barrier damage is insufficient to drive disease progression; (b) Prolonged and robust experimental CD4+ T cell depletion did not induce intestinal dysfunction in the absence of inflammation; (c) Prolonged experimental chemical damage of the mucosal epithelium induced progression only in a fraction of AGMs. As such, our results suggested that HIV/SIV disease progression is triggered by factors that go beyond mucosal damage. Meanwhile, in other studies, we have shown that (a) Dysbiosis correlates with gut dysfunction; (b) Gut microbiome changes induced by SIV in AGMs are markedly different from those observed in PWH, and may help creating an anti-inflammatory environment, maintaining gut barrier and preventing microbial translocation; (c) Dysbiotic flora translocate in progressive infections, and composition of the translocated microbiome determines the immunologic outcome in PWH on ART. These observations are the basis for our overarching hypothesis that microbiome is one of the main drivers of the outcome of SIV/HIV infection and that induction of major and persistent dysbiosis in AGMs in the presence of a dysfunctional epithelium may induce disease progression in this species. We will test this hypothesis in this competitive renewal to (a) Assess the impact of antibiotic-induced dysbiosis on gut integrity, inflammatory status and SIV disease progression in AGMs; (b) Assess the impact of dysbiosis occurring on a damaged gut (through DSS administration) in SIV-infected AGMs; (c) Assess the impact of dysbiosis occurring on a permeabilized gut and a liver with impaired capacity of filtering the translocated microbes (through alcohol administration). These experiments will directly assess the contribution of GI dysfunction to HIV disease progression and the contribution of microbiome in driving gut dysfunction. Our study is also highly significant in clinical settings and will establish the impact of antibiotic-induced dysbiosis in PWH who consume alcohol excessively. Our results will thus inform future therapeutic and behavioral strategies aimed at preserving gut integrity and avoiding disease progression.