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Journal of Virology, April 1999, p. 2938-2946, Vol. 73, No. 4
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Acute Hepatitis C Virus Structural Gene Sequences as Predictors of Persistent Viremia: Hypervariable Region 1 as a Decoy

Stuart C. Ray,1 Yu-Ming Wang,2 Oliver Laeyendecker,1 John R. Ticehurst,3,4 Stephen A. Villano,1 and David L. Thomas1,*

Departments of Medicine1 and Pathology,3 Johns Hopkins University School of Medicine, Baltimore, and Center for Devices and Radiological Health, U.S. Food and Drug Administration, Rockville,4 Maryland, and Department of Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing, Peoples' Republic of China2

Received 9 November 1998/Accepted 4 January 1999

We hypothesized that hepatitis C virus (HCV) persistence is related to the sequence variability of putative envelope genes. This hypothesis was tested by characterizing quasispecies in specimens collected every six months from a cohort of acutely HCV-infected subjects (mean duration of specimen collection, 72 months after seroconversion). We evaluated 5 individuals who spontaneously cleared viremia and 10 individuals with persistent viremia by cloning 33 1-kb amplicons that spanned E1 and the 5' half of E2, including hypervariable region 1 (HVR1). To assess the quasispecies complexity and to detect variants for sequencing, the first PCR-positive sample was examined by using a previously described method that combines heteroduplex analysis and analysis of single-stranded conformational polymorphisms. The ratio of nonsynonymous to synonymous substitutions (dN/dS) within each sample was evaluated as an indicator of relative selective pressure. Amino acid sequences were analyzed for signature patterns, glycosylation signals, and charge. Quasispecies complexity was higher and E1 dN/dS ratios (selective pressure) were lower in those with persistent viremia; the association with persistence was strengthened by the presence of a combination of both characteristics. In contrast, a trend toward higher HVR1 dN/dS ratios was detected among those with persistent viremia. We did not detect any such association for factors that may affect complexity such as serum HCV RNA concentration. HVR1 had a lower positive charge in subjects with persistent viremia, although no consistent motifs were detected. Our data suggest that HCV persistence is associated with a complex quasispecies and immune response to HVR1.

* Corresponding author. Mailing address: Division of Infectious Diseases, 720 Rutland Ave., Ross 1159, Baltimore, MD 21205. Phone: (410) 955-0349. Fax: (410) 614-9775. E-mail: dthomas{at}welchlink.welch.jhu.edu.

Journal of Virology, April 1999, p. 2938-2946, Vol. 73, No. 4
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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