The LHBsAg Protein and the Infectivity of the HDV Particles

For the HDV replication cycle to be completed, secreted virions must be targeted to uninfected cells. Therefore it was expected for the L-HBsAg protein, which mediates infectivity of the HBV virion (Gripon et al. 2005; Le Seyec et al. 1999), to be required as an integral component in the envelope of an infectious HDV particle. This was demonstrated in an in vitro culture system: particles coated with the S-HBsAg protein, or S-HBsAg and M-HBsAg, were notinfectiouswhentestedonprimaryhepatocytecultures. ButwhenL-HBs Ag was coexpressed with S-HBsAg, infectivity was restored (Sureau et al. 1993). We can presume that in using the same glycoprotein, namely L-HBsAg, as that used by HBV to mediate viral entry, HDV increases its chance of propagation because only HBV-susceptible cells could become infected with HDV. However this is not proven, and abortive infection may occur if HDV is driven to a hepatocyte that is not already infected by HBV, or is not to become infected. While it is clear that HBV does not make an efficient use of its budding system, it ensures infectivity to its virion because maturation and infectivity are linked to the same molecule, namely the L-HBsAg protein. This dual function of L-HBsAg has been mapped to two regions in the pre-S1 domain:

(a) a receptor binding site at the amino terminal end (Le Seyec et al. 1999); and

(b) a HBV nucleocapsid binding site at the carboxyl terminus, which should be dispensable for HDV (Bruss 1997). In contrast, taking full advantage of the HBV budding machinery, HDV uses all available S-HBsAg aggregates at the IC membrane, regardless of the presence of the L-HBsAg, to coat its RNP and bud. As a result, a significant amount of exported HDV virions is likely to be enveloped with S-HBsAg proteins only (or S-HBsAg and M-HBsAg), and thereby, to be noninfectious (Fig. 2). The minimum amount of L-HBsAg proteins in the HDV envelope to confer infectivity is unknown. Overall, the HDV life cycle depends on two HBV elements only: the S-HBsAg protein for the export of the RNP, and the L-HBsAg protein for entry into an uninfected hepatocyte (Fig. 3). With regard to the M-HBsAg protein, its role, which is still enigmatic in the HBV replication cycle, is not essential for in vitro assembly and infectivity of HDV (Bruss and Ganem 1991; Fernholz et al. 1993; Sureau et al. 1994; Wanget al. 1991). As for the details ofviral entry into the host cell, it seems reasonable to assume that HBV and HDV use the same cellular receptor on the human hepatocyte, but at present, its identity remains unknown. At a post-binding step, intracellular uptake is likely proceeding via receptor-mediated endocytosis (Kock et al. 1996), and internalization of HDV RNP and that of HBV nucleocapsid, most likely follow separate pathways in which S-HBsAg and L-HBsAg may participate. For both viruses, however, the outer shell has to be dismantled, and the interactions between envelope proteins and the inner cargo must be abolished.

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