# Hepatocyte-hepatic stellate cell axis in potentiation of alcohol and HIV-induced liver injury

> **NIH NIH F31** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2022 · $40,817

## Abstract

Project Summary
In the era of highly active antiretroviral therapy (ART), liver disease has become a common reason for
hospitalization and one of the leading causes of mortality among HIV positive individuals. The etiologies of
hepatotoxicity in HIV are multifaceted. HIV mono-infection, HIV co-infection with hepatotropic viruses (HBV
and HCV), HIV and alcohol-induced hepatotoxicity and ART-induced hepatotoxicity are known causes of liver
disease among HIV-infected individuals. Among all causes of hepatotoxicity, the mechanisms of alcohol-
induced hepatotoxicity in HIV-infected cells are unknown. Given that all HIV-infected individuals are on ART
due to high ART availability and accessibility, it becomes difficult to evaluate the single effects of alcohol on
the liver of HIV-infected individuals. That is why I am adopting an invitro system with the help of my mentors
(Drs. Osna and Poluektova) to explore alcohol-induced hepatotoxicity in HIV-infected hepatocytes. My
preliminary data under the supervision of my mentors has revealed the following findings: Alcohol metabolites
enhanced HIV accumulation in hepatocytes which triggers reactive oxygen species (ROS) that lead to
hepatocyte death via apoptotic pathway. When Hepatic Stellate Cells (HSC) were exposed to HIV-infected
apoptotic hepatocytes, an upregulation of profibrotic genes such as Col 1A1, TIMP 1 and TGFβ was
established after 2 hours of exposure. This implies that there might be a cross talk between hepatocytes and
HSC in the premises of HIV and alcohol via apoptotic hepatocytes which results in liver fibrosis. These
observations were confirmed in the liver of humanized mice exposed to HIV and alcohol. For therapeutic
purposes it has become necessary to understand the mechanisms of alcohol-induced hepatotoxicity in HIV-
infected cells. To understand this mechanism, we are confronted with research questions which seek to
understand the receptors for HIV entry into hepatocytes and the influence of alcohol metabolites to increase
HIV entry. Moreover, the impact of alcohol on HIV degradation in hepatocytes needs to be explored. It is not
known if hepatocyte death is due to apoptosis or other cell death mechanisms (such as necrosis or
necroptosis) are involved. Hence understanding the type of cell death mechanism will help devise strategies to
block/prevent the hepatocyte death, which mediates liver fibrosis. Also, we will explore the pathways involved
in the activation of profibrotic pathways to understand if blocking these pathways will prevent activation of
fibrotic genes. All the research questions will be tested in both in vitro and in vivo models. Skills that will be
gained during the 3-year period dedicated to completing the 3 aims of the research proposal are laboratory
techniques such as proteomics, flow cytometry, Real Time Polymerase Chain Reaction (RT PCR) for HIV
RNA, mRNA, HIV DNA, digital droplet PCR (ddPCR), flow cytometry, cell culture, and animal handling. During
this period,...

## Key facts

- **NIH application ID:** 10375398
- **Project number:** 5F31AA028743-02
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Moses O New-Aaron
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $40,817
- **Award type:** 5
- **Project period:** 2021-02-05 → 2022-12-16

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10375398

## Citation

> US National Institutes of Health, RePORTER application 10375398, Hepatocyte-hepatic stellate cell axis in potentiation of alcohol and HIV-induced liver injury (5F31AA028743-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10375398. Licensed CC0.

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