Pathogenesis of HIV and HBV Co-Infection in a Humanized Mouse Model

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Abstract Approximately 260 million people have chronic hepatitis B virus (HBV) infection, which leads to a spectrum of liver pathologies, including chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). HBV infection continues to be transmitted and is responsible for 40% of all HCC deaths worldwide. Almost 38 million people are infected with human immunodeficiency virus (HIV) globally, with approximately 10% of them chronically co- infected with HBV. Morbidity and mortality in HIV/HBV co-infection is higher than mono-infections and co- infection accelerates HBV-related liver disease with more frequent development of HCC, particularly when CD4 counts are low. Virologically suppressed co-infected individuals still experience increased liver fibrosis over time possibly due to ongoing chronic inflammation that occurs even during suppressed HIV infection. There are no cures for either HBV or HIV. Multiple unanswered questions remain regarding HIV/HBV co-infections, including the natural HBV disease course and assessment of liver disease, HBV reactivation after occult infection (HBV DNA in the absence of active replication), and improvements in antiviral treatments for both viruses. Hindering HIV/HBV co-infection pathogenesis and treatment research is the lack of a reliable animal model to study co-infection. Pre-clinical models are essential to evaluate mechanisms of infection as well as novel prevention methods, improved therapies, and curative strategies. We propose to characterize novel chimeric mice engrafted with a humanized liver and immune system from nonfetal human cells and tissues. In addition, we will evaluate HBV replication and liver disease progression during mono-infection and with either CD4 cell depletion or antiviral therapy. In addition, we will evaluate HIV/HBV co-infection with or without suppressive antiviral therapy. The goal is to improve the humanize mouse model to recapitulate human HBV mono-infection and HIV/HBV co-infection for the development of better therapies and curative strategies.