Structure of HDV and Hdv Rna

HDV is a small RNA virus consisting of spherical particles of about 36 nm in diameter. The virion itself is comprised of a short (1.7 kb) single-stranded, circular RNA that exists as a ribonucleoprotein complex with the only HDV-encoded protein, hepatitis delta antigen (HDAg). Together these form a roughly spherical core structure that is enveloped by hepatitis B surface antigen (HBsAg). There are approximately 70-200 HDAg molecules per RNA molecule (Ryu et al. 1993; Gudima et al. 2002).

The genomic form of HDV RNA does not encode protein. However, the complementary strand (antigenomic HDV RNA), which is detected in HDV-infected cells, contains a single open reading frame (ORF) that is responsible for the synthesis of the HDAg (protein-coding domain, Fig. 1). Thus, by definition, HDV is a negative-strand RNA virus. Both genomic and antigenomic HDV RNA species exhibit a high degree of intramolecular self-complementarity that allows the respective molecules to fold into an unbranched rod structure under nondenaturing conditions (Kos et al. 1986; Wang et al. 1986; Fig. 1). These semi-double-stranded structures probably serve to stabilize the RNA. Interestingly, these structures are strikingly similar to that adopted by viroid RNAs under the same conditions, although HDV

5' End HDAgmRNA nI1631 m7G cap 1



RNA Editing Site HDAg mRNA ntl015 nt934 -1-All

HDAg ORF Start ntl598

S-HDAg L-HDAg Stop Stop Poly A ntl014 nl954

AG Cleavage Site llllllllllllllllll llllllllllllllllllllllllllllll Mill ménr

70% Intramolecular Base Pairing

Putative G to AG Promoter

. nt68S G Cleavage Site

Protein Coding Domain

Viroid-Like Domain

Fig. 1 Genome organization of HDV RNA. Numbering is based on that of Wang et al. (1986). G, genomic HDV RNA; AG, antigenomic HDV RNA; S-HDAg, small hepatitis delta antigen; L-HDAg, large hepatitis delta antigen

RNA is three to four times larger. Also like some viroids, HDV RNA possesses ribozyme activities on both genomic and antigenomic strands that catalyze cis-cleavage of their respective RNAs (Kuo et al. 1988; Branch et al. 1989; viroid-like domain, Fig. 1). Both the genomic and antigenomic ribozyme activities are essential for HDV RNA replication (Macnaughton et al. 1993a). These similarities suggest an evolutionary relationship between HDV and vi-roids. However, in addition to size differences, what sets these two infectious agents apart is that only HDV has the ability to encode protein. At one end of the rod structure, a short region has been identified that exhibits RNA promoter activity in nuclear extracts (Beard et al. 1996). This region comprises of a stem-loop structure with several bulges, all of which are essential for replication (Beard et al. 1996; Putative G to AG Promoter, Fig. 1). Exactly how this promoter operates is unclear.

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