We have investigated the extent of hepatitis delta virus (HDV) genetic variability after serial passages in chimpanzees and woodchucks and between different human isolates. A complete HDV genome, isolated from a woodchuck liver, was cloned after five serial transmissions. The 1679 nucleotide long genome revealed only point mutations and a nucleotide divergence of 0.65% and 0.89% with previously published sequences of two epidemiologically related HDVs. We have obtained partial nucleotide sequences of two unrelated human HDV cDNAs by using the polymerase chain reaction. When compared to the woodchuck HDV strain and other previously reported isolates, a perfectly conserved region of 90 nucleotides was shown in the region encompassing the delta antigen antigenomic self-cleavage site. In woodchuck and human HDV strains, the two forms of delta protein (195 and 214 amino acids) were potentially expressed. Our study indicates that only a limited genetic variability is generated by several passages in animals despite significant modification of pathogenicity during these transmissions.


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