Alcohol potentiates HIV-induced hepatotoxicity via induction of lysosomal damage in hepatocytes

Life expectancy in people living with HIV (PLWH) has increased due to effective antiretroviral therapy (ART). Consequently, they survive longer, which increases co-morbidities. Liver disease is one of the leading co-morbidities in PLWH representing 18% of non-AIDS mortality. In addition, the incidence of alcohol abuse is twice as high in PLWH as compared to the general population. Generally, ethanol metabolism has been shown to aggravate the HIV-mediated liver damage. It enhances the accumulation of HIV in hepatocytes, which further aggravates oxidative stress and lysosomal damage/dysfunction. When oxidative stress is high, hepatocytes undergo apoptosis with the release of apoptotic bodies (ABs), while low oxidative stress causes exosome release from these cells. Engulfment of either ABs or exosomes by liver macrophages induces liver inflammation, and internalization of these extracellular vesicles (EVs) by hepatic stellate cells (HSC) promotes fibrosis development. The proposed anti-fibrotic therapy in PLWH with alcohol-use disorders (AUD) includes antioxidants, nanoparticles to block activation of pro-fibrotic pathways in HSC, and Obeticholic Acid (OCA).