Variation of hepatitis C virus following serial transmission: multiple mechanisms of diversification of the hypervariable region and evidence for convergent genome evolution

We have studied the evolution of hepatitis C virus (HCV) from a common sour ce following serial transmission from contaminated batches of anti-D immuno globulin. Six secondary recipients were each infected with virus from ident ifiable primary recipients of HCV-contaminated anti-D immunoglobulin. Phylo genetic analysis of virus E1/E2 gene sequences [including the hypervariable region (HVR)] and part of NS5B confirmed their common origin, but failed t o reproduce the known epidemiological relationships between pairs of viruse s, probably because of the frequent occurrence of convergent substitutions at both synonymous and nonsynonymous sites. There was no evidence that the rate at which the HCV genome evolves is affected by transmission events. Th ree different mechanisms appear to have been involved in generating variati on of the hypervariable region; nucleotide substitution, insertion/deletion of nucleotide triplets at the E1/E2 boundary and insertion of a duplicated segment replacing almost the entire HVR. These observations have important implications for the phylogenetic analysis of HCV sequences from epidemiol ogically linked isolates.