Research Project
10361609
Two cases of virus eradication (the ?Berlin patient? and the ?London patient?) demonstrated that a cure for HIV infection is feasible. Meanwhile, the burden of the HIV epidemic, which spreads unabated, as such that for every person living with HIV (PLWH) that starts antiretroviral therapy (ART), two new people become infected, fuels the global consensus that a cure for HIV is needed to curb the epidemic. Limitations towards eradication are: (i) HIV persistence in latently infected cells invisible to immune responses, (ii) inability of a damaged/exhausted immune system to eliminate HIV-infected cells, and (iii) a state of chronic inflammation (INFL) that persists despite ART. A better understanding of HIV reservoir seeding, maintenance and reactivation will identify new strategies for effective virus eradication. We reported that diet may interfere with SIV replication, immune activation (IA)/INFL, microbiome, basic metabolic features, and disease progression. Diet impacts directly and indirectly the host metabolism, modulating immune responses and the prognostic of HIV infection. We also reported a major impact of cell metabolic programing on all the key aspects that drive HIV persistence: (i) susceptibility to infection of HIV targets, persistence of infected cells, and the establishment of latency. (ii) Quality and magnitude of the immune responses to HIV. (iii) INFL associated to HIV infection, that contribute to reservoir maintenance (through continuous proliferation of latently infected cells) and its replenishment in tissues. Finally, we reported that metabolic alterations of the immune cell programing can preferentially occur in the gut. Altogether our results studies define an axis (diet?microbiome?nutritional metabolism?immunometabolism) that can dramatically impact HIV pathogenesis and shape HIV reservoir seeding, maintenance and reactivation, and which can be fueled by diet. Fasting and dietary interventions are being currently explored, alone or in combination with metabolic inhibitors in multiple other pathological conditions. We will probe the hypothesis that administration of a Western diet (WD, i.e., rich in fat and sugars) to rhesus macaques will fuel SIV reservoir formation, maintenance, and reactivation, through changes in T cells from the gut and related lymphoid and AdTs. We will assess the overall impact of the WD on host microbiome, metabolism, immune cell metabolic programing, immune responses, IA/INFL, and we will correlate these parameters with reservoir seeding, maintenance and reactivation. We will further determine whether gut T cells are responding to either a change in dietary sugars and lipids, plasma sugar and lipid increases trigerred by the WD, or to known changes in gut microbiome driven by WD. We will also therapeutically revert the WD-related processes with statins. Since the key alterations reported in our preliminary studies appeared to be centered by the gastrointestinal (GI) tract, the main site of HIV replication and CD4+ T cell depletion, we will focus on the gut and the adjacent lymphoid and AdTs. Blood will be used as a systemic comparator to alterations in the GI area. These studies may identify new strategies to curb the HIV reservoir, reverse the metabolic dysfunctions and control residual INFL.
