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Journal of Virology, April 2000, p. 3058-3066, Vol. 74, No. 7
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Hypervariable Region 1 Sequence Stability during Hepatitis C Virus Replication in Chimpanzees

Stuart C. Ray,1,* Qing Mao,1 Robert E. Lanford,2 Suzanne Bassett,2,dagger Oliver Laeyendecker,1 Yu-Ming Wang,1,Dagger and David L. Thomas1

Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205,1 and Department of Virology and Immunology, Southwest Regional Primate Research Center, Southwest Foundation for Biomedical Research, San Antonio, Texas 782272

Received 18 August 1999/Accepted 21 December 1999

The putative envelope 2 (E2) gene of hepatitis C virus (HCV) contains a highly variable region referred to as hypervariable region 1 (HVR1). We hypothesized that this genetic variability is driven by immune selection pressure, rather than representing the accumulation of random mutations in a region with relatively little functional constraint. To test this hypothesis, we examined the E2 sequence of a human inoculum that was passaged through eight chimpanzees, which appear to have a replicative rate (opportunity for chance mutation) similar to that of humans. Acute-phase plasma samples from a human (the inoculum) and six of eight serially infected chimpanzees were studied. For each, 33 cloned cDNAs were examined by a combined heteroduplex-single-stranded conformational polymorphism assay to assess quasispecies complexity and optimize selection of clones with unique gel shift patterns (clonotypes) for sequencing. The sequence diversity of HCV was significantly lower in the chimpanzees than in the humans, and during eight serial passages there was no change in the sequence of the majority clonotype from each animal examined. Similarly, the rates of protein sequence altering (nonsynonymous) substitution were lower in the chimpanzees than in the humans. These findings demonstrate that nonsynonymous mutations indicate selection pressure rather than being an incidental result of HCV replication.

* Corresponding author. Mailing address: Division of Infectious Diseases, 720 Rutland Ave., Ross 1159, Baltimore, MD 21205. Phone: (410) 955-0349. Fax: (410) 955-7889. E-mail: sray{at}jhmi.edu.

dagger Present address: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555.

Dagger Present address: Department of Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing, Peoples' Republic of China.

Journal of Virology, April 2000, p. 3058-3066, Vol. 74, No. 7
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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