Question

Explain how hepatitis delta virus regulates expression of the two forms of the delta antigen (understand the process of genome editing).

Answer 1

Hepatitis delta virus is a satellite virus that contains circular RNA of 1.7 kb as genetic material. HDB requires hepatitis B virus form assembly of virus. It can replicate independently of HBV but requires host RNA polymerases. The circular RNA of HDV encodes for a hepatitis delta antigen that exists in 2 forms. The smaller form is S-HDAg that has 195 amino acids. The larger form is L-LDAg with 214 amino acids and has an extra nuclear localization signal that is absent in S- HDAg. When the circular RNA is replicated by rolling circle method in the nucleus, a full length anti-genomic RNA is formed. This anti-genomic RNA undergoes transcription to form a 0.8 kb or 800 nucleotide containing anti-genomic-strand mRNA with 5′-cap and 3′-polyadenylated tail using different polymerases. This mRNA includes the open reading frame of HDAg. Translation of the 0.8 k anti-genomic strand mRNA leads to production of S-HDAg. This S-HDAg is required for replication of HDV.

RNA editing is involved in translation of HDAg ORF to L-HDAg. S-HDAg is formed as a shorter protein of 195 amino acid because anti-genomic strand HDAg mRNA has an amber termination codon. RNA editing is a mechanism other than alternative splicing that leads to formation of RNA species that codes for different proteins. In RNA editing, there is site specific modification of The RNA. In formation of L-HDAg, there is deamination of adenosine wherein the amino group is replaced by a keto group. Thus, the base will become a hydrogen bond acceptor rather than hydrogen bond acceptor. This leads to change in base pairing from Uracil to cytosine. Hence, the edited base now acts as G rather than as A. Hence, the amber termination codon is changed to a codon from tryptophan. This will lead to production of the longer L-HDAg instead to the S-HDAg. L-LDAg is formed during later stages of viral replication.