Inhibition of Cellular Factor TM6SF2 Suppresses Secretion Pathways of Hepatitis B, Hepatitis C, and Hepatitis D Viruses

Chronic viral hepatitis is caused by hepatitis B virus (HBV), hepatitis C virus (HCV), or hepatitis D virus (HDV). Despite different replication strategies, all of these viruses rely on secretion through the host endoplasmic reticulum-Golgi pathway, providing potential host targets for antiviral therapy. Knockdown of transmembrane 6 superfamily member 2 (TM6SF2) in virus cell culture models reduced secretion of infectious HCV virions, HDV virions, and HBV subviral particles. Moreover, in a cohort of people with hepatitis B, a TM6SF2 polymorphism (rs58542926 CT/TT, which causes protein misfolding and reduced TM6SF2 in the liver) correlated with lower concentrations of subviral particles in blood, complementing our previous work showing decreased HCV viral load in people with this polymorphism. In conclusion, the host protein TM6SF2 plays a key role in secretion of HBV, HCV, and HDV, providing the potential for novel pan-viral agents to treat people with chronic viral hepatitis. Chronic hepatitis viruses HBV, HCV, and HDV all rely on endoplasmic reticulum-Golgi secretion. Knocking down the host gene TM6SF2 in cell culture models reduces secretion of HBV, HCV, and HDV particles, offering the potential for pan-viral therapies to treat chronic hepatitis. Graphical Abstract