# Cooperative mechanisms of HIV-enhanced liver fibrogenesis in HBV Coinfection

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $709,110

## Abstract

Project Summary/Abstract
HIV infects about 40 million people worldwide, among whom approximately 10% harbor chronic
hepatitis B virus (HBV) co-infection. The progression of chronic HBV to cirrhosis, end-stage liver
disease, or hepatocellular carcinoma is accelerated in HIV coinfection compared to chronic HBV
monoinfection. Nucleos(t)ide analogues (NAs) including entecavir and tenofovir are currently
approved for the treatment of chronic HBV infection. In HIV coinfection, despite HBV
suppression with NAs, there is still evidence for more severe liver injury and fibrosis compared
with NA-suppressed HBV monoinfection. However, the mechanisms by which HIV increases
HBV replication and HBV-induced liver fibrosis are not well characterized. One of the major
obstacles in HIV-HBV coinfection study has been the lack of a robust animal or co-culture model.
We have extensive experience in the study of HIV-induced liver fibrosis in HCV-HIV coinfection
and have parlayed this experience into relevant models for HIV-HBV co-infection. Using
HIV/HBV mono-culture and novel transwell and spheroid co-culture models (up to 3 lines)
developed in our laboratory, we have found that HIV increases HBV replication, HBV cccDNA
levels, and enhances HBV-induced fibrosis-related gene expression in HBV HepAD38, HBV-
infected NTCP-HepG2 and LX2 HSC cells. We have found that HBV and HIV infection each
induce cytokine disturbances that could contribute to fibrosis. Separately, we have found that
HIV enhances pyruvate production, which in turn promotes hepatic fibrosis. We hypothesize that
HIV cooperatively promotes HBV-related liver fibrosis through (1) alterations in profibrogenic
cytokine secretion and (2) changes in pyruvate status. To evaluate these hypotheses, we will
use in vitro mono-culture, and transwell and spheroid co-culture models and verify these
findings in liver and blood from in vivo humanized mice HIV/HBV coinfection models. These
Aims are feasible, mechanistically grounded, and highly likely to yield results that will lead to
clarification of HIV-HBV-host interactions. They are also likely to yield an array of new targets
for the development of treatments designed to enhance HBV functional cure and preventing
HIV-accelerated HBV liver disease progression.

## Key facts

- **NIH application ID:** 10651715
- **Project number:** 5R01AI155140-04
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** RAYMOND T CHUNG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $709,110
- **Award type:** 5
- **Project period:** 2020-07-15 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10651715

## Citation

> US National Institutes of Health, RePORTER application 10651715, Cooperative mechanisms of HIV-enhanced liver fibrogenesis in HBV Coinfection (5R01AI155140-04). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10651715. Licensed CC0.

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