# Novel mouse models of hepatitis B virus infection and replication

> **NIH NIH R01** · WAKE FOREST UNIVERSITY HEALTH SCIENCES · 2024 · $662,025

## Abstract

Summary
Hepatitis B virus (HBV) is a common cause of liver diseases such as acute and chronic hepatitis, liver fibrosis,
cirrhosis, and hepatocellular carcinoma (HCC). HBV infection continues to pose a major threat to global public
health, affecting more than 250 million people worldwide. Although licensed vaccines can effectively prevent new
HBV infection, they do not offer therapeutic benefits to the hundreds of million people already infected with HBV.
The biggest challenge to cure chronic hepatitis B is the lack of therapeutics to eliminate HBV covalently closed
circular DNA (cccDNA), which is responsible for HBV persistence. Current standard antiviral therapies consisting
of interferon and/or nucleoside analogs can suppress HBV replication but do not significantly affect the level of
HBV cccDNA. Thus, there is an urgent need to discover and develop new classes of antiviral drugs capable of
eliminating HBV infection. Over the years, the search for a cure of chronic hepatitis B has been hampered by the
lack of robust cell culture systems of HBV propagation and small animal models of HBV infection and replication.
The discovery of sodium taurocholate cotransporting polypeptide (NTCP) as an HBV receptor has made it
possible to develop cell culture models of HBV infection. However, NTCP per se does not confer HBV
susceptibility in transgenic mice, suggesting other co-receptors that may be needed for more efficient HBV
infection in vivo. Through preliminary studies, we have found that human apolipoprotein E (apoE) and
apoE-binding receptors such as heparan sulfate proteoglycans (HSPGs) and the low-density lipoprotein receptor
(LDLR) family proteins promote HBV infection. More significantly, our preliminary data suggest that
co-expression of NTCP with human apoE and LDLR in the proprotein convertase subtilisin/kexin type 9
(PCSK9)-deficient mice could confer HBV susceptibility. Strikingly, inoculation of NTCP/apoE3/LDLR/PCSK9-/-
mice with HBV derived from HBV-transgenic mice expressing human apoE3 resulted in a high HBV viremia
(~106 genome copy equivalents/mL) in the mouse sera after one week of HBV inoculation. We hypothesize that
the cell tropism of HBV is not only determined by its receptor NTCP but also by host factors promoting HBV
infection, transcription, and replication. The overall goal of this application is to develop robust mouse models of
HBV infection and replication for investigation of HBV infection, transcription, replication, pathogenesis, and host
immune response to HBV infection as well as for evaluation of HBV-specific antiviral drugs and therapeutic
strategies in vivo. Our specific aims are: 1) to develop an immunocompetent mouse model of HBV infection and
replication; 2) to construct novel mouse models of HBV persistence; and 3) to develop an immunodeficient
mouse model of HBV infection and to determine host immune control of HBV infection. The successful
completion of this application will have a profound impact on HBV rese...

## Key facts

- **NIH application ID:** 10913911
- **Project number:** 1R01AI183855-01
- **Recipient organization:** WAKE FOREST UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** GUANGXIANG George LUO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $662,025
- **Award type:** 1
- **Project period:** 2024-06-21 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10913911

## Citation

> US National Institutes of Health, RePORTER application 10913911, Novel mouse models of hepatitis B virus infection and replication (1R01AI183855-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10913911. Licensed CC0.

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