Molecular Biology

Structure

The hepatitis D virus consists of a circular RNA genome and δ antigen (δAg) proteins encased in an envelope embedded with Hepatitis B surface antigen (HBsAg). The virion is 35nm in diameter, and the genome is 1.7-kb long.

http://www.cdc.gov/ncidod/diseases/hepatitis/slideset/hep_d/slide_1.htm

Viral Life Cycle

--attachment to the host cell involves HbsAg

--genomic RNA and δAg are uncoated and transported to the nucleus

--genomic RNA is transcribed to produce antigenomic RNA

--δAg transcripts are capped and polyadenylated

--antigenomic RNA is cleaved into unit-length RNA circles

--genomic RNA is transcribed from the antigenomic RNA

--small and large δAg associate with genomic RNA

--viral proteins interact with HBsAg

--viruses assemble and bud

Replication

Unlike hepatitis B replication, HDV does not require reverse transcription or DNA intermediates. Circular RNA serves as a template for host RNA-dependent RNA polymerase. Replication occurs via a rolling mechanism. A small percentage of the transcripts are capped and translated into small and large δAgs, while the rest become antigenomic RNA. These antigenomic RNAs in turn become templates for translation of genomic RNA. The RNA is stabilized inside the cell because it can fold into rod-like structures with about 70% of their nucleotides in Watson and Crick base pairs.

The genome and antigenome of HDV have an interior domain of about 100 nucleotides which act as a ribozyme. After transcription, genomic and antigenomic RNAs are autocleaved into unit-length linear RNAs. These linear RNAs then form circles, more stable structures which can also function as transcriptional templates.

Delta Antigen

Delta antigens come in two varieties: large and small. Small δAg is required to initiate HDV genome replication, while the large δAg is essential for viral assembly. Large δAg is identical to small δAg except for an additional 19 amino acids at one end. After transcription of the antigenomic RNA, an ADAR (adenosine deaminase acting on RNA) edits the stop codon of the small δAg, turning it into the codon for tryptophan (UAG à UGG). This allows translation of the large δAg.

Large δAg appears to inhibit genomic RNA synthesis. However, the large δAg RNA is incorporated into the HDV virion. A recent study has shown that large δAg is prevented from inhibiting viral synthesis due to an increased rate of mutation near its promoter sequence. These additional mutations appear to be triggered by the editing of the stop codon in the small δAg. This increases the replication efficiency of the genome and also regulates the amount of large δAg in the infected cell.