Molecular Biology and Evolution, Vol 16, 1622-1632, Copyright © 1999 by Society for Molecular Biology and Evolution
JC Wu, TY Chiang, WK Shiue, SY Wang, IJ Sheen, YH Huang and WJ Syu
Recombination between RNA sequences plays a role in the fast evolution of a
few viruses. There has been no report on hepatitis D virus (HDV)
recombination. In this study, we analyzed genetic recombination of HDV and
its possible impact on evolution and clinical course. The aligned HDV
sequences allowed us to construct a phylogenetic tree which supported the
notion of distinct lineages of HDV. The tree was also used in the analysis
of recombination using partial likelihoods assessed through optimization.
Nine segments of the HDV genome with significant levels of genetic
recombination were detected. Five segments were in the hypervariable
region, and four were in the delta- antigen- coding region. None could be
found in the well-conserved autocleavage region that is essential for
replication. Recombination occurred both between and within types. The
results of this study indicated that the remarkable variation in HDV
genomic sequences, particularly in the hypervariable region, among
different genotypes may at least partly result from multiple episodes of
genetic recombination during evolution. Genetic recombination may play a
significant role in increasing genetic diversity. Importantly, a genetic
recombination (nt 1082-1093) occurred in one of the immunogenic domains of
hepatitis delta virus antigen recognized by human and woodchuck antibodies
(amino acids 174-195). Genetic recombination also occurred at another
segment between nt 1517 and 1535, which was close to one of the predicted
T- cell epitopes (amino acids 26-41). In longitudinal analysis of HDV
genomes at different time points during chronic infection, novel dominant
HDV strains with amino acid changes at these epitopes usually emerged after
severe hepatitis attacks. In the comparison of HDV clones during or shortly
after flare-up of liver disease, Ka/Ks ratios of > 1 were frequently
found, suggesting Darwinian positive selection. Therefore, recombination in
these two segments may play an important role for HDV in the evasion of
immunity.
ORIGINAL ARTICLE
Recombination of hepatitis D virus RNA sequences and its implications
Department of Medicine, Veterans General Hospital, Taipei, Taiwan. jcwu@vghtpe.gov.tw
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