Abstract
People with human immunodeficiency virus-hepatitis B virus (HIV-HBV) co-infection have faster rates of liver disease progression and an increase in hepatocellular carcinoma compared to people with HBV mono-infection. Given that HIV can infect multiple cells in the liver, including hepatocytes, we hypothesized that HIV will impact HBV replication through HIV viral proteins that can impact HBV replication either directly or indirectly, via effects on cellular pathways. Following infection of sodium taurocholate co-transporting polypeptide (NTCP)-expressing HepG2 cells with HBV and vesicular stomatitis virus G protein (VSV.G)-pseudotyped HIV, we found that productive HIV infection led to a twofold upregulation of HBV surface (HBs) mRNA and a marked increase in intracellular production and cellular retention of HBs antigen (HBsAg). Overexpression of HIV Tat protein, but not other HIV proteins, by DNA plasmid transfection in the HBV-producing cell line AD38 significantly stimulated HBs mRNA expression. This could be rescued by CDK9 inhibition with BAY-1251152. This study provides new insights into the mechanisms by which HIV directly impacts HBV replication and has implications for understanding adverse liver outcomes in people living with HIV and HBV.IMPORTANCEPeople with both human immunodeficiency virus (HIV) and hepatitis B virus (HBV) face faster liver disease progression and a higher risk of liver cancer than those with HBV alone. This study investigated how HIV affects HBV replication in liver cells and found that HIV infection increases the production of a key HBV surface protein (HBsAg) by enhancing the expression of its gene (HBs). This effect is driven by the HIV Tat protein. Notably, blocking the CDK9 pathway prevented this increase, suggesting a possible explanation for the adverse liver outcomes in co-infected individuals. Our findings have implications for interventions aiming to cure HIV through latency reversal, as these interventions can specifically increase the Tat protein. Future exploratory treatment strategies, such as Tat inhibitors, could play a role in the management of people with HIV and HBV at high risk of liver disease.