A. Background on HDV Replication: The Hepatitis delta virus genome consists of a circular, unbranched RNA, similar to plant viroids. The mechanisms and nature of Hepatitis D replication have been a mystery for many years: unlike most RNA viruses (aside from plant viroids), it does not encode an RNA dependent RNA polymerase, and so must rely on cellular enzymes or components to replicate its genome. Cellular polymerases (Pols) replicate the viral genome. A number of recent findings have advanced our knowledge of the replication mechanisms of deltaviruses.

Chang J, Gudima SO, Taylor JM. 2005. Evolution of hepatitis delta virus RNA genome following long-term replication in cell culture. J of Virology. 79(21): 13310-6. Pubmed

It has been shown that HDV can replicate continuously in culture for up at least one year if provided with a source of HDAg-S mRNA. Change et al examined the nature of the changes to the nucleotide sequence of HDV after a year of replication in culture. They found the majority of changes to be single nucleotide substitutions, primarily base transitions, rather than insertions or deletions. Much of this mutation was the result of editing by cellular adenosine deaminase (ADAR enzymes), and a small percentage from errors in transcription. Most importantly, HDV sequences after one year were just as effective in replication as the original sequences. The findings suggest that HDV in chronic hepatitis D can continue to replicate and may be just as virulent a year or longer into the infection as in the initial stages of infection.

Wang, T., and M. Chao. 2005. RNA Recombination of Hepatitis Delta Virus in Natural Mixed-Genotype Infection and Transfected Cultured Cells. J of Virology. 79(4): 2221-2229.Pubmed

While RNA recombination has been demonstrated in animal RNA viruses that encode their own polymerase and in viroids, it has not been demonstrated in HDV, which depends on cellular RNA polymerase. Wang and Chao demonstrate that RNA recombination of HDV is both possible in culture and occurs naturally in individuals infected with multiple HDV genotypes. One proposed mechanism is template switching by the cellular polymerase during replication at certain secondary structures in the RNA (such as hairpins). The results suggest a powerful mechanism for HDV heterogeneity that could easily lead to new HDV strains with new properties. Moreover, recombinants between viral and cellular genetic material may also be a possibility.

Replication of HDV. Viral particles consist of HDV RNA (black lines) and HDV antigen (blue) encapsidated by HBsAg (red).
Picture From: Heller T, Hoofnagle JH. (2003). Denying the wolf access to sheep's clothing. Journal of Clinical Investigation. 112: 319-21.