The bifunctional role of interleukin-1Β in modulating hepatitis B virus replication and host defense during HIV/HBV coinfection

The National Institute of Allergy and Infectious Diseases awarded Emory University $100,228 under the Allergy and Infectious Diseases Research program (CFDA 93.855) on February 11, 2027.

The award funds research into the bifunctional role of interleukin-1B in modulating hepatitis B virus replication and host defense during HIV/HBV coinfection. The research addresses how sustained interleukin-1B exposure—a hallmark of HIV-associated systemic inflammation—may enhance HBV replication through p38 MAPK-dependent signaling pathways, thereby accelerating liver disease progression in co-infected individuals. The investigator's preliminary data reveal that while interleukin-1B limits early HBV infection through downregulation of viral entry receptors and activation of antiviral responses, treating established HBV infection paradoxically increases viral replication in hepatocyte models, an effect blocked by p38 MAPK inhibition but not NF-KB inhibition. This bifunctional mechanism is significant given that approximately 2.7 million people living with HIV are co-infected with HBV, and liver-related morbidity and mortality remain disproportionately high despite widespread use of HBV-active antiretroviral therapy.

Performance of work occurs in Atlanta, Georgia. The period of performance extends from the award date through September 14, 2029. The project grant is assistance type funding supporting basic and translational research on infectious and allergic diseases.

Abstract

Hepatitis B virus (HBV) infection remains a major global health burden, affecting 254 million people worldwide and causing over one million deaths annually from cirrhosis and hepatocellular carcinoma. Among people living with HIV, approximately 2.7 million are CO-infected with HBV. Despite widespread use of HBV-active antiretroviral therapy, liver-related morbidity and mortality remain disproportionately high. HIV infection is characterized by chronic systemic inflammation and immune dysregulation; however, how this inflammatory environment directly influences HBV replication and liver disease progression remains unclear. Interleukin-1Β (IL-1Β) is a key inflammatory mediator that is elevated during HIV infection and is strongly induced by microbial translocation via the GUT-liver axis, thereby driving ongoing activation of liver-resident immune cells. Previous studies have shown that IL-1Β limits early HBV infection by downregulating the viral entry receptor ntcp and activating antiviral host responses. While my initial data confirm these antiviral effects during the early stage of infection, they also reveal a new bifunctional role for IL-1Β: treating established HBV infection paradoxically increases viral replication in HEPG2-ntcp cells and mouse-passaged primary human hepatocytes, as evidenced by higher levels of intracellular HBV DNA, hbcag, and hbeag. Notably, this pro-viral effect can be blocked by inhibition of P38 mapk, but not NF-ΚB, indicating a novel non-canonical IL-1Β signaling pathway. Based on these findings, I hypothesize that sustained IL-1Β exposure, a hallmark of HIV-associated systemic inflammation, enhances HBV replication through P38 mapk-dependent and NF-ΚB-independent induction of pro-viral host factors, thereby accelerating liver disease progression in HIV/HBV CO-infected individuals. This hypothesis will be tested with two aims: (1) defining the specific post-entry stages of HBV replication that IL-1Β enhances, including effects on cccdna transcription, pgrna stability, and viral DNA synthesis, using complementary HBV infection and replication models along with physiologically relevant primary hepatocyte-kupffer cell CO-cultures; and (2) identifying the signaling pathway and host factors involved by employing crispr-based genetic modifications of key signaling components (rela and MAPK14), measuring NF-ΚB pathway activity with reporter assays, and uncovering key candidates through unbiased proteomic profiling of IL-1Β-treated MAPK14 knockout versus non- targeting control cells. This work is innovative because IT redefines IL-1Β from an antiviral cytokine to a context- dependent enhancer of HBV replication during chronic infection. The proposed research will uncover a new mechanism linking HIV-related inflammation to HBV disease progression. IT may identify druggable host targets within inflammatory signaling pathways to reduce liver disease burden in HIV/HBV CO-infected individuals. This study will provide mechanistic insights into how inflammation promotes viral persistence, supporting my development into an independent researcher focused on viral-host interactions during chronic infections.