Nucleotide sequence andmutation rateoftheH strain ofhepatitis Cvirus

Patient H isanAmerican patient whowas infected withhepatitis C virus (HCV)in1977. Thepatient became chronically infected andhasremained soforthepast 13years. Inthis study, wecompared thenucleotide and predicted aminoacid sequences oftheHCVgenome obtained fromplasma collected in1977withthat collected in1990. We find that thetwoHCVisolates differ at123ofthe4923(2.50%) nucleotides sequenced. Weestimate that themutation rate of theH strain ofHCV is-1.92x10-3 basesubstitutions per genome site peryear. Thenucleotide changes wereexclusively basesubstitutions andwereunevenly distributed throughout thegenome. Arelatively highrate ofchange wasobserved in theregion oftheHCVgenome thatcorresponds tothenon- structural protein 1gene region offlaviviruses, where 44of960 (4.6%) nucleotides weredifferent. Within this region there was a39-nucleotide domaininwhich28.2%ofthenucleotides differed between thetwoisolates. Incontrast, relatively few nucleotide substitutions wereobserved inthe5'noncoding region, where only 2of276(0.7%) nucleotides weredifferent. Ourresults suggest that themutation rate oftheHCVgenome issimilar tothat ofother RNAviruses andthat genes appear tobeevolving atdifferent rates within thevirus genome. Theprincipal etiologic agentofparenterally transmitted non-A, non-B(NANB)hepatitis recently wasmolecularly cloned fromtheplasma ofanexperimentally infected chim- panzee (1). Theagent hasbeennamedhepatitis C virus (HCV). Tests forantibody toHCV(2) or,moredirectly, the HCVgenome (3)clearly demonstrate that HCVisthemajor etiological agent ofposttransfusion NANB hepatitis. TheHCV genomeisalinear, positive-stranded RNA