A. Background on HDV Replication: The
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.
It has been shown that HDV can replicate continuously in culture for up
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.
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
and occurs naturally in individuals infected with multiple HDV
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
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.