IMPACT OF HIV ANTIRETROVIRAL THERAPY ON THE EUKARYOTIC GUT VIROME AND HOST HEALTH

Abstract

Antiretroviral therapy (ART) is prescribed to people living with HIV (PLWH) or to individuals taking it as pre-exposure prophylaxis (PrEP). In PLWH, ART can significantly reduce viral loads to undetectable levels and prevent Acquired Immune Deficiency Syndrome (AIDS). Despite ART efficacy, PLWH are still at elevated risk of multiple chronic diseases, including metabolic syndrome (MetS). The microbiome of PLWH has been shown to differ from that of HIV-negative individuals, even when receiving ART, suggesting a potential role for an ART-modulated gut microbiome in chronic disease pathogenesis. However, whether ART itself can directly modulate gut microbiome/virome, and specifically endogenous gut eukaryotic viruses, remains unknown. Here, we raise the hypothesis that ART itself has direct collateral impacts on gut eukaryotic viruses and that this modulation contributes to the increased risk of non-infectious disease. In this thesis work, I assessed the impact of antiretrovirals (ARVs) given individually (abacavir (ABC), dolutegravir (DTG), lamivudine (3TC), emtricitabine (FTC), tenofovir alafenamide (TAF), and tenofovir disoproxil fumarate (TDF)) or in combination (cART, TDF/FTC/DTG) on the metabolic health of HIV-naïve mice. Individual ARVs, as well as cART, exacerbated diet-induced weight gain (3TC, DTG, and TAF) and glucose intolerance (3TC, TAF, and FTC). Preliminary profiling revealed that DTG and FTC altered the gut microbiome while DTG and TDF altered the virome. To explore the mechanisms through which ART alters the virome, specifically eukaryotic viruses, I aimed to determine how different ARVs impact eukaryotic virus-host cell interactions in vitro. A universal concentration of ARVs (ABC, DTG, 3TC, FTC, TAF, and TDF) that does not affect Caco-2 and BHK-21 cell viability was determined. Viral plaque assays were also calibrated and preliminary experiments with ARV treatment was performed. Overall, this work suggests an association between the direct impact of ARVs on the gut microbiome/virome and MetS, and provides a framework to explore the mechanisms of eukaryotic virus modulation by ART