HIV Tat and HBV HBx in HIV/HBV Coinfection-associated Liver Disease

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SUMMARY Globally, an estimated 250 million people are chronically infected with hepatitis B virus (HBV) and an estimated 38 million people are infected with human immunodeficiency virus type 1 (HIV-1). 10-25% of HIV-infected individuals are co-infected with HBV. A chronic HBV infection is the most common risk factor for hepatocellular carcinoma (HCC). HIV infection also has pathological effects in the liver and increases the risk for HCC in HIV/HBV co-infection. The molecular mechanisms underlying liver disease in HIV/HBV co-infection are poorly understood. When treated with antiviral therapy (AT), either for mono- or co-infection, the viral load of HIV-1 and HBV can be undetectable. For HIV, this pushes the disease to a chronic state that is associated with increased comorbidities, including several types of cancer. Approved anti-HIV and anti-HBV AT do not block viral protein synthesis in HIV- or HBV-infected cells, and the HIV Tat and HBV HBx proteins are expressed even with AT. HBx is required for in vivo HBV replication, regulates cell signals, such as apoptotic signals, that influence carcinogenesis, and causes HCC in HBx-transgenic mice. Tat also has a role in chronic HIV disease, can alter apoptotic signals, and causes HCC in Tat-transgenic mice. HBV infects hepatocytes; however, whether HIV infects hepatocytes in a natural infection is unclear, and if so, studies indicate this is inefficient. In an HIV-infected individual, Tat is in the circulating blood even with AT, and in an HIV/HBV co-infection, circulating Tat could provide signals in the liver to enhance HBV-induced HCC. Kupffer cells (KCs) are liver-resident macrophages that can be infected by HIV and would be expected to secrete pro-inflammatory cytokines and Tat in the liver. We hypothesize that in an HIV/HBV co-infection, the effects of Tat, as an extracellular protein or in combination with other cellular macromolecules from HIV-infected KCs, enhance HBx-driven cellular signals that regulate HBV replication and/or hepatocyte apoptosis, leading to an elevated risk for liver disease, including HCC, as compared to mono-infection. The goal of this proposal is to determine whether cooperative HBx and Tat activities affect HBV replication and apoptosis in HBV-infected hepatocytes and define mechanisms underlying cooperative effects. We will: 1) Determine how Tat cooperates with HBx to affect HBV replication and hepatocyte apoptosis; and 2) Determine how HIV-infected KCs affect HBV replication and hepatocyte apoptosis and how this is linked to Tat activities. We will use HBV- or HBx-expressing recombinant adenovirus (AdHBx)-infected cultured primary human hepatocytes (PHHs). Tat will be provided as exogenous purified protein, as a component of conditioned cell culture medium from HIV-infected KCs, or from co-culture of HIV-infected KCs with HBV- or AdHBx-infected PHHs. We will assess how Tat, alone or in combination with factors produced in HIV-infected KCs, affects HBV replication and hepatocyte apoptosis. These studies should lead to translational opportunities, such as developing inhibitors for interacting Tat and HBx signals or diagnostics for increased HCC risk.