Inhibition of cellular factor TM6SF2 suppresses secretion pathways of Hepatitis B, Hepatitis C and Hepatitis D viruses

Abstract Introduction Chronic viral hepatitis, a leading cause of global deaths, is caused by three enveloped viruses from distinct families: hepatitis B virus, hepatitis C virus, and hepatitis D virus (HBV, HCV, and HDV). Despite having different replication strategies, all three viruses rely on secretion through the host endoplasmic reticulum-Golgi pathway to maintain chronic infection. Thus, targeting key genes in this pathway offers the potential for pan-viral therapies to treat chronic hepatitis. Methods Transmembrane 6 superfamily member 2 (TM6SF2) was knocked down using siRNA in cell culture models of HBV, HCV and HDV and virus secretion was measured. The effect of TM6SF2 polymorphisms on virus blood markers was examined in a cohort of people with hepatitis B. Results Knockdown of TM6SF2 in cell culture models reduced secretion of infectious HCV virions, HDV virions and HBV subviral particles. Moreover, we show that a TM6SF2 polymorphism (rs58542926 CT/TT, which causes protein misfolding and reduced TM6SF2 in the liver) correlates with lower concentrations of subviral particles in blood from people with hepatitis B, complementing our previous work showing decreased HCV viral load. Conclusions The host protein TM6SF2 is a novel drug target due to its key role in secretion of HBV, HCV and HDV. This provides the exciting potential for pan-viral agents to treat all people with chronic viral hepatitis.