Lipid raft therapy – a novel therapeutic approach for HIV-associated cardiometabolic co-morbidities

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Abstract HIV infection is accompanied by a number of co-morbidities, with cardio-metabolic complications being among the most prominent. Current antiretroviral therapy (ART) controls the HIV load and reverses immunodeficiency, but does not eliminate HIV-associated co-morbidities. The mechanisms responsible for the persistence of cardio- metabolic co-morbidities in ART-treated HIV-infected subjects with an undetectable virus load remain unknown, preventing the development of therapeutic treatments. Our studies identified HIV protein Nef as the main contributor to viral effects on cholesterol metabolism and potential cardiac phenotypes. Other recent reports from several groups demonstrated that HIV-infected cells release extracellular vesicles (EVs) containing Nef, which were found in the plasma of ~50% of ART-treated HIV-infected individuals with undetectable viral load. We showed that Nef-containing EVs, but not EVs produced by cells infected with Nef-deficient HIV, triggered perturbations of cellular cholesterol metabolism in uninfected macrophages, increased abundance and changed the properties of lipid rafts in these cells, and led to potentiation of inflammatory responses. These findings led us to a hypothesis that changes to lipid rafts induced by Nef EVs may underlie the mechanism of cardio- metabolic co-morbidities of HIV disease, and therefore these co-morbidities can be treated by agents blocking or reversing the Nef-induced changes of lipid rafts. We named this treatment approach “lipid raft therapy”. In the proposed project we will test this hypothesis by pursuing the following Specific Aims. In Aim 1, we will characterize the effects of Nef-containing EVs on the composition and structure of the lipid rafts and will relate these changes to functional properties. We will also determine whether treatments blocking the effect of Nef EVs on lipid rafts can reverse the Nef-induced functional effects. In Aim 2, we will investigate the association between Nef EVs and cardio-metabolic co-morbidities and will test lipid raft-targeting treatment approaches in vivo. We will use apoE-/- mice transgenic for HIV or infected with murine HIV (EcoHIV) to model HIV-associated atherosclerosis and metabolic impairment. In Aim 3, we will determine whether levels of exNef in plasma of people living with HIV (PLWH) correlate with markers of cardio-metabolic co-morbidities, whether blood monocytes of PLWH exhibit lipid rafts changes, and whether these changes can be reversed ex vivo by the lipid raft therapy tested in Aims 1 and 2. Together, these studies will describe a new mechanism of HIV-associated co-morbidities and will investigate new therapeutic treatments targeting this mechanism, thus producing both a basic science and a translational impact on the field.