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Journal of Virology, October 2008, p. 9417-9424, Vol. 82, No. 19
0022-538X/08/$08.00+0     doi:10.1128/JVI.00896-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Comparative Analysis of Nearly Full-Length Hepatitis C Virus Quasispecies from Patients Experiencing Viral Breakthrough during Antiviral Therapy: Clustered Mutations in Three Functional Genes, E2, NS2, and NS5a {triangledown}

Zekuan Xu,1,3 Xiaofeng Fan,1,2* Yanjuan Xu,1 and Adrian M. Di Bisceglie1,2*

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Saint Louis University School of Medicine, St. Louis, Missouri 63104,1 Saint Louis University Liver Center, Saint Louis University School of Medicine, St. Louis, Missouri 63104,2 Department of Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China3

Received 29 April 2008/ Accepted 18 July 2008

Viral breakthrough is a recognized response pattern to interferon-based antiviral therapy in patients with chronic hepatitis C virus (HCV) infection. The emergence of drug-resistant HCV quasispecies variants is assumed to be a major mechanism responsible for viral breakthrough. By using a long reverse transcription-PCR protocol recently developed in our lab, multiple nearly full-length HCV quasispecies variants were generated from 9.1-kb amplicons at both the baseline and breakthrough points in two patients experiencing viral breakthrough. Comparative analyses of consensus dominant quasispecies variants revealed that most mutations, occurring at the time of breakthrough, involved three functional viral genes, E2, NS2, and NS5a. Interestingly, similar mutation patterns were also observed in minor quasispecies variants at baseline. These three genes had the highest values of average amino acid complexity at the HCV 1a population level. No single amino acids were identified to be associated with viral breakthrough. Taken together, at the near-full-length HCV genome level, our data suggested that viral breakthrough might be attributed to the selection of minor quasispecies variants at the baseline with or without additional mutations during antiviral therapy. Furthermore, the pattern for mutation clustering indicated potential mutation linkage among E2, NS2, and NS5a due to structural or functional relatedness in HCV replication.

* Corresponding author. Mailing address: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Saint Louis University School of Medicine, 3635 Vista Avenue, St. Louis, MO 63110. Phone: (314) 977-7833. Fax: (314) 577-8125. E-mail for X. Fan: fanx{at}slu.edu. E-mail for A. M. Di Bisceglie: dibiscam{at}slu.edu

{triangledown} Published ahead of print on 30 July 2008.

Journal of Virology, October 2008, p. 9417-9424, Vol. 82, No. 19
0022-538X/08/$08.00+0     doi:10.1128/JVI.00896-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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