Molecular interactions between hepatitis B virus and delta virus

Abstract

As a deficient virus due to the lack of envelope proteins, hepatitis D virus (HDV) causes chronic or fulminant "delta hepatitis" only in people with simultaneous hepatitis B virus (HBV) infection. HBV encodes three types of surface proteins known as small (S), medium (M) and large (L) envelope proteins. All three types of HBV surface antigens (HBsAgs) are present on HDV virions. The envelopment process of HDV occurs through interactions between the HDV ribonucleoprotein (RNP) complex and HBV HBsAgs. While HBsAg is the only protein required by HDV, the exact interaction sites between the S protein and pre-mature HDV are not well defined yet. In fact, these sites are distributed along the S protein with some hot spots for the envelopment process. Moreover, in most clinically studied samples, HDV infection is associated with a dramatically reduced HBV viral load, temporarily or permanently, while HBsAg resources are available for HDV packaging. Thus, beyond interacting with HBV envelope proteins, controlling mechanisms exist by which HDV inhibits HBV-DNA replication while allowing a selective transcription of HBV proteins. Here we discuss the molecular interaction sites between HBsAg and the HDV-RNP complex and address the proposed indirect mechanisms, which are employed by HBV and HDV to facilitate or inhibit each other's viral replication. Understanding molecular interactions between HBV and HDV may help to design novel therapeutic strategies for delta hepatitis.

Keywords: Ag loop; Hepatitis B virus; Hepatitis B virus surface antigens; Hepatitis D virus; Hepatitis D virus antigen; Liver cirrhosis; Viral hepatitis.

Figure 1

Hepatitis D virus-ribonucleoprotein complex interaction with S-hepatitis B virus surface antigen. Schematic representation of L- and S-HBsAg locations in the ER membrane and the interaction sites with the HDV-RNP complex. The Asn-146 glycosylation site is highlighted by a star. About half of the residues remain non-glycosylated at this site. A cytosolic orientation has been suggested for the non-glycosylated Ag loop, which may interfere with HBsAg-HDAg interaction. L-HDAg mediates HDV assembly at the late stage of viral replication through forming connections with HDV-RNA, S-HDAg and HBsAg. Ag loop: Antigenic loop; CYL I, II: Cytosolic loop I, II; ER: Endoplasmic reticulum; L-/ S-HBsAg: Large and small hepatitis B virus surface antigens; L-/ S-HDAg: Large and small hepatitis D virus proteins; RNP: Ribonucleoprotein; TMD: Transmembrane domain.