Hepatitis B Virus infection initiates with a large surface protein-dependent binding to heparan sulfate proteoglycans

Abstract

Contrary to many other viruses, the initial steps of the Hepatitis B virus (HBV) infection, including attachment, specific receptor interaction and membrane fusion, are unsolved. Using the susceptible HepaRG cells as an in vitro cell culture system, we here report that HBV entry into hepatocytes requires the large envelope protein (L)-dependent interaction with cell-surface glycosaminoglycans (GAG). HBV infection was abrogated by incubation of virions with heparin, but not with lower sulfated GAGs. Polycationic substances prevented infection as well, however by addressing cellular components. Enzymatic removal of cellular GAGs or the obstruction of GAG synthesis abolished HBV infection and, moreover, led to a reduction of viral attachment. Biochemical interaction studies showed selective binding of L-protein rich virions to heparin and furthermore revealed the important role of the preS1-domain of the L-protein in this process. In conclusion, the attachment of HBV to heparan sulfate proteoglycans initializes the multi-step entry process of HBV and cannot be circumvent by interaction with other cellular receptor components.