Alcohol suppression of IFN immunity supports HBV replication in hepatocytes 2305

Abstract Description Hepatitis B virus (HBV) infection can lead to end-stage liver disease. Alcohol increases HBV morbidities that follow chronic infections. The interplay between alcohol, HBV, and innate immunity is incompletely understood. Relationships between ethanol metabolism and HBV replication were studied during crosstalk between hepatocytes (Hep) and macrophages. Ethanol metabolism was addressed using an acetaldehyde-generating system (AGS) with HepAD38 and HepG2.2.15 HBV+ cells. Both cells do not metabolize ethanol. Hep exposure to AGS upregulated HBV RNA, DNA, and cccDNA. AGS suppressed STAT1 phosphorylation and APOBEC3G in Hep and macrophages. Supernatants from interferon alpha (IFNα) treated macrophages passed to HBV+ Hep reduced HBV markers and increased IFN-stimulated gene (ISGs) expression in both AGS-treated and untreated HepG2.2.15 cells. However, ethanol and GW4869 (an exosome inhibitor), when given to macrophages, reversed the effects. This demonstrated communications between IFNa-activated macrophages and HBV+ Hep cells. Additionally, IFNβ and IFN type 1 production were altered by AGS in HBV-replicating Hep due to reduced IRF3 phosphorylation and MAVS/STING expression. We conclude that ethanol metabolism supports HBV replication by suppressing IFN-associated innate immunity protection by ISGs in Hep and by affecting macrophage function. Funding Sources NIH P50AA030407-5129 Topic Categories Viral Immunology (VIR)