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Journal of Virology, November 2009, p. 11456-11466, Vol. 83, No. 22
0022-538X/09/$08.00+0 doi:10.1128/JVI.00884-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
Full-Length Characterization of Hepatitis C Virus Subtype 3a Reveals Novel Hypervariable Regions under Positive Selection during Acute Infection
Isla Humphreys,1
Vicki Fleming,1
Paolo Fabris,2
Joe Parker,3
Bodo Schulenberg,3
Anthony Brown,1
Charis Demetriou,1
Silvana Gaudieri,4,5
Katja Pfafferott,4
Michaela Lucas,4
Jane Collier,6
Kuan-Hsiang Gary Huang,1
Oliver G. Pybus,3
Paul Klenerman,1 and
Eleanor Barnes1*
Oxford NIHR Biomedical Research Centre and Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom,1 Department of Infectious Diseases and Tropical Medicine, S. Bortolo Hospital, Vicenza, Italy,2 Department of Zoology, University of Oxford, Oxford, United Kingdom,3 Centre for Clinical Immunology and Biomedical Statistics, Royal Perth Hospital, Perth, Australia,4 School of Anatomy and Human Biology and Centre for Forensic Science, University of Western Australia, Nedlands Australia,5 John Radcliffe Hospital, Oxford, United Kingdom6
Received 1 May 2009/ Accepted 31 July 2009
Hepatitis C virus subtype 3a is a highly prevalent and globally distributed strain that is often associated with infection via injection drug use. This subtype exhibits particular phenotypic characteristics. In spite of this, detailed genetic analysis of this subtype has rarely been performed. We performed full-length viral sequence analysis in 18 patients with chronic HCV subtype 3a infection and assessed genomic viral variability in comparison to other HCV subtypes. Two novel regions of intragenotypic hypervariability within the envelope protein E2, of HCV genotype 3a, were identified. We named these regions HVR495 and HVR575. They consisted of flanking conserved hydrophobic amino acids and central variable residues. A 5-amino-acid insertion found only in genotype 3a and a putative glycosylation site is contained within HVR575. Evolutionary analysis of E2 showed that positively selected sites within genotype 3a infection were largely restricted to HVR1, HVR495, and HVR575. Further analysis of clonal viral populations within single hosts showed that viral variation within HVR495 and HVR575 were subject to intrahost positive selecting forces. Longitudinal analysis of four patients with acute HCV subtype 3a infection sampled at multiple time points showed that positively selected mutations within HVR495 and HVR575 arose early during primary infection. HVR495 and HVR575 were not present in HCV subtypes 1a, 1b, 2a, or 6a. Some variability that was not subject to positive selection was present in subtype 4a HVR575. Further defining the functional significance of these regions may have important implications for genotype 3a E2 virus-receptor interactions and for vaccine studies that aim to induce cross-reactive anti-E2 antibodies.
* Corresponding author. Mailing address: Peter Medawar Building for Pathogen Research, South Parks Rd., Oxford OX1 3SY, United Kingdom. Phone: 44 (0) 1865 271 199. Fax: 44 (0) 1865 281 890. E-mail: ellie.barnes{at}ndm.ox.ac.uk
Published ahead of print on 9 September 2009.
Journal of Virology, November 2009, p. 11456-11466, Vol. 83, No. 22
0022-538X/09/$08.00+0 doi:10.1128/JVI.00884-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
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