Background

There has been a long-running search for the cellular receptor of hepatitis B virus (HBV). This search has been hampered by the lack of cell lines permissive for HBV infection and the difficulty of producing HBV vectors with selectable reporter genes, akin to vectors used to determine the HIV and hepatitis C virus host cell receptors. The discovery many years ago that primary duck hepatocytes are susceptible to duck HBV (DHBV) infection and, subsequently, that primary human hepatocytes are susceptible to infection by HBV, and the satellite hepatitis delta virus (HDV), opened the door for investigations on viral and cellular determinants of virus entry. The DHBV model seemed particularly suitable, because duck primary hepatocytes (dPHCs) are easy to prepare and a large fraction can be productively infected in culture with DHBV. Moreover, virus-binding experiments demonstrated high-affinity binding sites or receptors on duck hepatocytes and, importantly, showed that these binding sites exhibit species- and tissue-specificity, consistent with the restricted host range and tissue tropism characteristic of the Hepadnaviridae.1 ,2 In the meantime, Tupaias (treeshrews), belonging to the family Tupaiidae, and not considered primates, were shown to be susceptible to HBV infection.3 Tupaia primary hepatocyte cultures (tPHCs) are also permissive for HBV and HDV infection, and provided a new tool in the search for the HBV receptor.4 Finally, lentiviruses pseudotyped with HBV envelope proteins were shown to infect human primary hepatocytes (hPHCs).5

Using these and other model systems, different laboratories over the past 25 years reported the identification of host proteins that could bind to HBV, DHBV or recombinant envelope components of these viruses.6 One of the best-studied receptor candidates was carboxypeptidase D (CPD), a transmembrane protein that binds to DHBV and to its envelope protein, L, in a host species-specific manner.7––9 However, CPD …