# Development of humanized transgenic mice for HBV/HIV co-infection studies

> **NIH NIH R21** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2020 · $190,625

## Abstract

ABSTRACT
A better understanding of the interplay between innate and adaptive immune responses to hepatitis B virus
(HBV) in human immunodeficiency virus (HIV-1)-induced immune system impairment is crucial for the
development of new antiviral immune therapeutics. Mice that carry human immune system and are affected by
HIV-1 have great promise in in vivo experimental models for studying HBV/HIV co-infection. Despite current
progress in humanized mouse models, species differences preclude efficient “collaboration” of the human
immune system in a shell of mouse non-immune cells. We propose to create a new model that possesses the
most crucial set of human genes for lymphoid tissue development, namely the lymphotoxin beta receptor
(hLTβR), two chemokines involved in T- and B-cell zone establishment (hCCL21, hCXCL13), and a thymic
stromal lymphopoietin (hTSLP). In this application, we propose replacing mouse genes with hLTβR, hCCL21,
hCXCL13, and hTSLP to develop a new model suitable for future HBV/HIV coinfection studies. We will employ
Easi-CRISPR gene editing, our recently developed and highly robust method, to create the proposed mouse
model(s). In this strain, we expect efficient generation of human follicular helper cells, which are a key component
for the establishment of adaptive immunity to HBV. The ability to study the immune response to HBV in the
presence of HIV-1 infection will be a new step in modeling HBV/HIV coinfection. All genetic manipulations will
be performed on a strain of mice that already has human IL-34 transgene on a NOG background. The rational
for NOG-hIL34 transgenic mice is that it efficiently supports human tissue-resident macrophages (including
Kupffer cells) and introduces lymphoid tissue organizing human factors, which will provide a strong support for
development of follicular helper T cells and the adaptive immune response to HBV antigens. We will validate the
ability of the new humanized strain to control HIV-1 infection and the effects of infection on immune responses
to HBsAg. Such a model will also provide a means for the development of therapeutics and address
pathobiological paradigms of HBV/HIV coinfection previously not possible to study in vivo.
 Our immediate goal is to improve the existing model to create a new, invaluable tool for researchers that
can support a wide range of HBV/HIV coinfection studies. By testing the efficacy of human immune system
development and function in all four modifications, we can determine whether to combine all genotypes into one
mouse strain. As the next step in development, we will introduce TK-NOG background for efficient transplanting
of human hepatocytes. Our long-term goal is to facilitate studies of innate and adaptive immunity in HBV/HIV-1
coinfection.

## Key facts

- **NIH application ID:** 9882941
- **Project number:** 5R21AI143394-02
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Channabasavaiah Gurumurthy
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $190,625
- **Award type:** 5
- **Project period:** 2019-03-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9882941

## Citation

> US National Institutes of Health, RePORTER application 9882941, Development of humanized transgenic mice for HBV/HIV co-infection studies (5R21AI143394-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9882941. Licensed CC0.

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