Impact of a Glucagon-Like Peptide-1 Receptor Agonist administration on SIV/HIV pathogenesis and ART

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

Investigators

Abstract

Antiretroviral therapy (ART) administration to people living with HIV (PWH) associates significant weight gain and dramatic (>30%) increase in visceral and abdominal adipose tissue (AdT). Obesity and AdT hypertrophy are accompanied with inflammation, type 2 diabetes and cardiovascular disease. Since metabolic disease is now diagnosed in >70% of PWH on ART, this is a major clinical burden and threat to lifespan. Visceral AdT (VAT) represents a major HIV reservoir, the persistence of which thwarts virus eradication. In our pigtailed macaque (PTM) model of HIV infection, ART administration mirrors with high fidelity the major elements of metabolic disease in PWH: accumulation of inflamed VAT, weight gain, high levels of oxidized HDLs, increased plasma levels of free fatty acids, hypercholesterolemia and hypertriglyceridemia. CA-vDNA levels in cells isolated from fat confirmed AdT as a key SIV reservoir. We thus hypothesize that by increasing VAT and altering lipid metabolic profiles, HIV/SIV and ART cause AdT infiltrating T cells and macrophages to become dysfunctional, through adipose lipid-driven changes to immune cell metabolism, activation, and proliferation. These immune cell dysfunctions promote inflammation and virus persistence in AdT. We will use our PTM model, a first line ART used in PWH, and an FDA approved weight loss drug to dissect the host immunological and metabolic processes involved in the persistence of the AdT SIV reservoir, residual INFL and associated comorbidities. We will: 1) Assess specific changes of T-cell and macrophage metabolism by SIV and ART in relation to immune cell activation, proliferation, differentiation and function in AdT. 2) Measure the antiviral cellular immune responses in AdT. 3) Assess the cellular sources of inflammation in AdT. 4) Measure the size of AdT virus reservoir. 5) Establish the lipid profile induced by SIV/ART in blood and AdT. 6) Test the ability of plasma and AdT-derived lipids to directly evoke changes in T cells and macrophage subsets. We will thus establish how VAT size and lipid composition lead to changes in AdT T-cell homeostasis and CTL frequency and function versus the persistence of viral reservoir. We will also assess how dysfunctional T cells and macrophages induce AdT inflammation. We will then use a GLP-1 agonist to alter the size and distribution of AdT and modify the metabolism and function of the immune cells that infiltrate AdT. The GLP-1 agonist will be administered either after months of ART administration or concomitantly to ART initiation to either alleviate or prevent the adverse metabolic effects induced by ART in the AdT. The impact of our intervention will be assessed in AdT and systemically. These mechanistic studies can only be performed in models of SIV and ART, and target mechanisms pharmacologically relevant for obesity and inflammation in the general population. Their successful completion will provide proof-of-concept data showing that the clinical management of the PWH would benefit from targeting AdT and other metabolic disturbances induced by infection and ART.