Recombination of hepatitis D virus RNA sequences and its implications

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) recombina tion. In this study, we analyzed genetic recombination of HDV and its possi ble impact on evolution and clinical course. The aligned HDV sequences allo wed us to construct a phylogenetic tree which supported the notion of disti nct lineages of HDV. The tree was also used in the analysis of recombinatio n using partial Likelihoods assessed through optimization. Nine segments of the HDV genome with significant levels of genetic recombination were detec ted. Five segments were in the hypervariable region, and four were in the d elta-antigen- coding region. None could be found in the well-conserved auto cleavage region that is essential for replication. Recombination occurred b oth between and within types. The results of this study indicated that the remarkable variation in HDV genomic sequences, particularly in the hypervar iable region, among different genotypes may at least partly result from mul tiple episodes of genetic recombination during evolution. Genetic recombina tion may play a significant role in increasing genetic diversity. Important ly, a genetic recombination (nt 1082- -1093) occurred in one of the immunog enic domains of hepatitis delta virus antigen recognized by human and woodc huck 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 domina nt HDV strains with amino acid changes at these epitopes usually emerged af ter severe hepatitis attacks. In the comparison of HDV clones during or sho rtly after flare-up of liver disease, K-a/K-s 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 im munity.