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Updated: Jul 24, 2025
Establishment of the Dual Humanized TK-NOG Mouse Model for HIV-associated Liver Pathogenesis
Published on: September 11, 2019
Persistent hepatitis B virus and HIV coinfections in dually humanized mice engrafted with human liver and immune
Glenn Hogan1, Benjamin Y Winer1, James Ahodantin2,3
1Lewis Thomas Laboratory, Department of Molecular Biology, Princeton University, Princeton, New Jersey, USA.
Insights
Researchers developed a novel humanized mouse model to study chronic hepatitis B (CHB) and human immunodeficiency virus (HIV) coinfection. This model supports HBV and HIV infection, enabling studies on immune responses and new therapeutic development.
Area of Science:
- Hepatology
- Immunology
- Virology
Background:
- Chronic hepatitis B (CHB) is a significant global health issue caused by the hepatitis B virus (HBV).
- HBV infection can lead to severe liver conditions like fibrosis, cirrhosis, and hepatocellular carcinoma.
- Coinfection with human immunodeficiency virus (HIV) exacerbates liver disease in CHB patients, yet immunocompetent animal models are scarce.
Purpose of the Study:
- To develop and validate a dually humanized mouse model for studying HBV infection and HBV-HIV coinfection.
- To investigate HBV-induced immune responses in a humanized system.
- To provide a platform for preclinical testing of immunotherapeutics for HBV and HBV-HIV coinfection.
Main Methods:
- Engrafting mice with human immune system components and human liver tissue.
- Infecting humanized mice with HBV and assessing viral load and replication.
- Analyzing human immune cell responses, including CD8+ T cell activation.
- Establishing and utilizing dually humanized mice for HBV and HIV coinfection studies.
Main Results:
- Humanized mice supported HBV infection, with partial control observed through human immune cells, indicated by reduced viremia and liver replication.
- HBV infection induced priming and expansion of human HLA-restricted CD8+ T cells with an activated phenotype.
- The dually humanized model successfully supported persistent coinfections with both HBV and HIV.
Conclusions:
- The developed dually humanized mouse model effectively supports HBV infection and HBV-HIV coinfection.
- This model allows for the analysis of immune dysregulation in HBV-HIV coinfection.
- It serves as a valuable preclinical platform for evaluating novel immunotherapies against HBV and HIV coinfection.
Abstract:
Chronic hepatitis B (CHB), caused by hepatitis B virus (HBV), remains a major medical problem. HBV has a high propensity for progressing to chronicity and can result in severe liver disease, including fibrosis, cirrhosis, and hepatocellular carcinoma. CHB patients frequently present with viral coinfection, including human immunodeficiency virus type (HIV) and hepatitis delta virus. About 10% of chronic HIV carriers are also persistently infected with HBV, which can result in more exacerbated liver disease. Mechanistic studies of HBV-induced immune responses and pathogenesis, which could be significantly influenced by HIV infection, have been hampered by the scarcity of immunocompetent animal models. Here, we demonstrate that humanized mice dually engrafted with components of a human immune system and a human liver supported HBV infection, which was partially controlled by human immune cells, as evidenced by lower levels of serum viremia and HBV replication intermediates in the liver. HBV infection resulted in priming and expansion of human HLA-restricted CD8+ T cells, which acquired an activated phenotype. Notably, our dually humanized mice support persistent coinfections with HBV and HIV, which opens opportunities for analyzing immune dysregulation during HBV and HIV coinfection, and preclinical testing of novel immunotherapeutics.
