# Identifying and modulating therapeutic targets in a model of hepatitis B

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $548,297

## Abstract

PROJECT SUMMARY:
 Hepatitis B virus (HBV) is a small, partially double-stranded DNA virus that causes acute and chronic
hepatitis. An estimated 400 million people are chronically infected worldwide, many suffering early death due to liver
failure and primary liver cancer (HCC). The chance of resolving HBV infection is age dependent: approximately 90%
of neonatal infections become chronic, whereas at least 90% of adult infections are cleared spontaneously. It is
generally accepted that a broad and diverse adaptive immune response is important in clearing acute HBV infection.
However, why an individual generates, or fails to generate, a favorable response, and why this capability varies with
age, is just beginning to be understood.
 The study of HBV immunopathogenesis has been limited because HBV only infects outbred species whose
immune systems are difficult to examine and it does not infect mice, the species in which most of the tools to study
immune mechanisms have been developed. My laboratory has developed transgenic mouse models of primary
HBV infection that mimic key differences in HBV clearance and persistence in humans, including the age-related
dichotomy in human HBV infection outcome. This model has allowed us to address fundamental questions in HBV
biology: 1. Why is the immune response and disease outcome different depending on the age of the individual at
the time of infection? 2. What are the immune mechanisms that facilitate viral control, and how do these differ from
the immune mechanisms that lead to chronic viral infection? 3. Can immune modulation of pathways identified to
be important in effective HBV immunity tilt ineffective immune responses toward viral control?
 Our collective data using this model and our correlative studies in humans, demonstrate that immune
priming to HBV occurs in the liver, and that effective immune priming requires orchestrated formation of leukocyte
clusters that are anchored by macrophages and monocytes. Effective HBV immunity requires hepatic TFH cell
priming and IL-21 production in the liver, where it is essential for optimal generation of specific CD8+ T and B cell
responses that are crucial for viral clearance. Furthermore, maturation of liver APCs and their age-dependent
expression of the chemokine CXCL13 is crucial for B cell differentiation and class-switching, while age-dependent
expression of the co-stimulatory ligand OX40L explains differences in TFH priming and IL-21 production in the liver.
 While these new data begin to help us formulate a new paradigm to explain age-dependent HBV
persistence and to identify therapeutic targets, there are many unanswered questions related to the cells and
pathways involved in the formation of hepatic leukocyte structures and the priming of effective immunity. Our
proposal explores the hypothesis that a resident hepatic population of group 3 innate lymphoid cells (ILC3s) is
important for the development of lymphoid organization and/or the priming of effe...

## Key facts

- **NIH application ID:** 10218014
- **Project number:** 5R01AI139762-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** JODY L BARON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $548,297
- **Award type:** 5
- **Project period:** 2018-08-16 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10218014

## Citation

> US National Institutes of Health, RePORTER application 10218014, Identifying and modulating therapeutic targets in a model of hepatitis B (5R01AI139762-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10218014. Licensed CC0.

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