The Metabolic Crossroads: Decoding Fentanyl's Impact on HIV/HBV Co-infection for Targeted Interventions

About This Grant

Project Summary The convergence of the opioid crisis and HIV epidemic has created an unprecedented public health emergency, with approximately 10% of people living with HIV also co-infected with hepatitis B virus (HBV). While HIV/HBV co-infection already accelerates liver disease progression and increases mortality, the introduction of synthetic opioids like fentanyl has dramatically worsened outcomes through mechanisms that remain poorly understood. This proposal addresses a critical knowledge gap at the intersection of substance use disorder and HIV co- infections. The overarching goal of this project is to systematically investigate how fentanyl exposure fundamentally alters HIV/HBV co-infection dynamics at the molecular level and to identify targetable metabolic pathways for therapeutic intervention. We will leverage pioneering biomimetic cell culture models, including mouse-passed primary human hepatocytes (mpPHH) with 100% HBV infection rates and physiologically relevant cccDNA levels, combined with HIV-infected CD4+ T cells in innovative co-culture systems. Our project goals are to characterize fentanyl's impact on viral replication dynamics and identify metabolic pathways contributing to altered pathogenesis through comprehensive multi-omics analyses, and to investigate fentanyl-mediated drug- drug interactions with HIV/HBV antivirals using both 2D co-cultures and 3D liver organoid models, with validation in humanized mice harboring genetically modified human liver grafts. This application is highly relevant to HIV and substance use disorder research as it directly addresses the biological mechanisms underlying poor clinical outcomes in people who use drugs (PWUD) with HIV/HBV co-infection. By focusing on CYP3A4-mediated metabolism, the primary pathway for both fentanyl and many antivirals, we will uncover dangerous drug-drug interactions and altered therapeutic efficacy that currently compromise treatment success. Our findings will enable development of personalized therapeutic strategies that account for the unique metabolic challenges faced by PWUD, ultimately improving viral suppression rates and reducing liver disease progression in this vulnerable population. This paradigm-shifting approach treats substance use not as a behavioral comorbidity but as a central biological variable that fundamentally reshapes viral pathogenesis and treatment response.