12-week Dolutegravir treatment marginally reduces energy expenditure but does not increase body weight or alter vascular function in a murine model of Human Immunodeficiency Virus infection

Combination antiretroviral therapy (cART) has markedly increased life expectancy in people with HIV (PWH) but has also resulted in an increased prevalence of cardiometabolic disorders, whose etiopathology remains illdefined. Notably, the respective contribution of cART and HIV-derived proteins to obesity and vascular alterations remain poorly understood. Therefore, we investigated the individual and combined effects of HIV-proteins and of the integrase strand transfer inhibitor Dolutegravir (DTG) on body composition and vascular reactivity. Male wildtype (WT) and HIV transgenic (Tg26) mice, received DTG or vehicle for 12 weeks. Viral proteins expression in Tg26 mice lowered fat mass, increased heat production, and induced a 2-fold increase in brown adipose tissue (BAT) uncoupling protein 1 (UCP1) expression. DTG increased the expression of markers of adipogenesis in adipocytes in culture, but also reduced heat production and BAT UCP1 and UCP3 expression in Tg26 mice. DTG increased food intake, fat percentage and protected from lean mass reduction in Tg26 mice only. However, DTG did not increase body weight in either WT or Tg26 mice. Viral protein expression reduced acetylcholine (endothelium)-mediated relaxation by 14% in mesenteric arteries preconstricted with phenylephrine. However, DTG did not impair nor improve endothelium-dependent relaxation. Together, these data indicate that DTG's effects on food intake, adipogenesis and energy expenditure are insufficient to increase body weight, even in the presence of HIV-proteins, suggesting that body weight gain in PWH involves additional factors likely including other cART components and pre-existing comorbidities. Moreover, these data rule out DTG as a source of vascular disorders in PWH.