Alcohol Metabolism Potentiates HIV-Induced Hepatotoxicity: Contribution to End-Stage Liver Disease

Authors

Murali Ganesan, Veterans Affairs Nebraska-Western Iowa Health Care SystemFollow
Moses New-Aaron, Veterans Affairs Nebraska-Western Iowa Health Care SystemFollow
Raghubendra Singh Dagur, Veterans Affairs Nebraska-Western Iowa Health Care SystemFollow
Edward Makarov, University of Nebraska Medical CenterFollow
Weimin Wang, University of Nebraska Medical CenterFollow
Kusum K. Kharbanda, Veterans Affairs Nebraska-Western Iowa Health Care SystemFollow
Srivatsan Kidambi, University of Nebraska - LincolnFollow
Larisa Y. Poluektova, University of Nebraska Medical CenterFollow
Natalia A. Osna, University of Nebraska Medical CenterFollow

ORCID IDs

Moses New-Aaron

Raghubendra Singh Dagur

Kusum K. Kharbanda

Srivatsan Kidambi

Larisa Y. Poluektova

Natalia A. Osna

Date of this Version

2019

Document Type

Article

Citation

Biomolecules 2019, 9, 851

Comments

© 2019 by the authors.

Open access

doi:10.3390/biom9120851

Abstract

In an era of improved survival due to modern antiretroviral therapy, liver disease has become a major cause of morbidity and mortality, resulting in death in 15–17% of human immunodeficiency virus (HIV)-infected patients. Alcohol enhances HIV-mediated liver damage and promotes the progression to advanced fibrosis and cirrhosis. However, the mechanisms behind these events are uncertain. Here, we hypothesize that ethanol metabolism potentiates accumulation of HIV in hepatocytes, causing oxidative stress and intensive apoptotic cell death. Engulfment of HIV-containing apoptotic hepatocytes by non-parenchymal cells (NPCs) triggers their activation and liver injury progression. This study was performed on primary human hepatocytes and Huh7.5-CYP cells infected with HIV-1ADA, and major findings were confirmed by pilot data obtained on ethanol-fed HIV-injected chimeric mice with humanized livers. We demonstrated that ethanol exposure potentiates HIV accumulation in hepatocytes by suppressing HIV degradation by lysosomes and proteasomes. This leads to increased oxidative stress and hepatocyte apoptosis. Exposure of HIV-infected apoptotic hepatocytes to NPCs activates the inflammasome in macrophages and pro-fibrotic genes in hepatic stellate cells. We conclude that while HIV and ethanol metabolism-triggered apoptosis clears up HIV-infected hepatocytes, continued generation of HIV-expressing apoptotic bodies may be detrimental for progression of liver inflammation and fibrosis due to constant activation of NPCs.