Graduation Date

Fall 12-16-2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Environmental Health, Occupational Health, and Toxicology

First Advisor

Natalia A. Osna

Second Advisor

Larisa Y. Poluektova

Abstract

Human Immunodeficiency Virus (HIV) remains a global threat, with approximately 38.4 million active infections and 33 million HIV-related deaths since the first case. While many may be tempted to think of HIV as a relic of the past, emerging data suggests otherwise. By the end of 2021, approximately 1.5 million HIV incidences and 650 000 mortalities were reported globally. The etiologies of HIV-related mortality are numerous. Liver disease is one of the leading etiologies of HIV-related mortality, especially in recent times of antiretroviral therapy (ART)-induced longevity among people living with HIV (PLWH). While co-infections with hepatotropic viruses notoriously contribute to the frequently observed liver disease among HIV-infected individuals, alcohol abuse is another significant trigger of liver disease. In fact, alcohol hepatitis is among the knottiest liver disease etiologies because the liver is not just a significant target for alcohol. Still, alcohol abuse is twice more frequent among PLWH than in HIV-uninfected individuals. Recent work from our group has shown that in the absence of ART, alcohol metabolites enhance HIV accumulation in hepatocytes, which consequently induces massive oxidative hepatocyte apoptosis. Internalization of HIV-and-malonaldehyde (MDA)-containing hepatocyte apoptotic bodies (AB) by hepatic stellate cells (HSC) induces profibrotic activation which leads to a progression of liver fibrosis.

The pathomechanisms of alcohol-induced liver injury among PLWH are yet to be understood. Hence, this dissertation was focused on deciphering the mechanisms of alcohol and HIV-induced hepatocyte apoptosis (Chapter 2) and the subsequent HSC activation after the internalization of MDA-and HIV-containing AB (Chapter 3). To ameliorate alcohol and HIV-induced liver injury, an anti-fibrotic drug, obeticholic acid (OCA) was employed (Chapter 4). Our findings indicate that metabolically generated acetaldehyde damages lysosomes and likely prevents their repair and restoration, thereby leading to hepatocyte apoptosis (Chapter 2). Hence, this results in the formation of HIV-and MDA-containing hepatocyte apoptotic bodies internalized by HSC through the AXL receptor. The consequent HSC profibrotic activation was mediated by ROS-dependent JNK-ERK1/2 and IL6 triggering of JAK-STAT3 pathways (Chapter 3). While these mechanisms explained liver fibrosis frequently observed among alcohol-abusing PLWH, in an in vitro model, OCA attenuated profibrotic activation of HSC via the JAK-STAT3 pathway (Chapter 4).

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2022 Copyright, the authors

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