This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Zhou, Y.
Right arrow Articles by Lin, C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Zhou, Y.
Right arrow Articles by Lin, C.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, January 2008, p. 110-120, Vol. 52, No. 1
0066-4804/08/$08.00+0     doi:10.1128/AAC.00863-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Phenotypic Characterization of Resistant Val36 Variants of Hepatitis C Virus NS3-4A Serine Protease{triangledown}

Yi Zhou, Doug J. Bartels, Brian L. Hanzelka, Ute Müh, Yunyi Wei, Hui-May Chu, Ann M. Tigges, Debra L. Brennan, B. Govinda Rao, Lora Swenson, Ann D. Kwong, and Chao Lin*

Vertex Pharmaceuticals Incorporated, 130 Waverly Street, Cambridge, Massachusetts 02139

Received 3 July 2007/ Returned for modification 7 August 2007/ Accepted 1 October 2007

In patients chronically infected with hepatitis C virus (HCV) strains of genotype 1, rapid and dramatic antiviral activity has been observed with telaprevir (VX-950), a highly selective and potent inhibitor of the HCV NS3-4A serine protease. HCV variants with substitutions in the NS3 protease domain were observed in some patients during telaprevir dosing. In this study, purified protease domain proteins and reconstituted HCV subgenomic replicons were used for phenotypic characterization of many of these substitutions. V36A/M or T54A substitutions conferred less than eightfold resistance to telaprevir. Variants with double substitutions at Val36 plus Thr54 had ~20-fold resistance to telaprevir, and variants with double substitutions at Val36 plus Arg155 or Ala156 had >40-fold resistance to telaprevir. An X-ray structure of the HCV strain H protease domain containing the V36M substitution in a cocomplex with an NS4A cofactor peptide was solved at a 2.4-Å resolution. Except for the side chain of Met36, the V36M variant structure is identical to that of the wild-type apoenzyme. The in vitro replication capacity of most variants was significantly lower than that of the wild-type replicon in cells, which is consistent with the impaired in vivo fitness estimated from telaprevir-dosed patients. Finally, the sensitivity of these replicon variants to alpha interferon or ribavirin remained unchanged compared to that of the wild-type.

* Corresponding author. Mailing address: Department of Infectious Diseases, Vertex Pharmaceuticals Incorporated, 130 Waverly Street, Cambridge, MA 02139. Phone: (617) 444-6202. Fax: (617) 444-6210. E-mail: chao_lin{at}vrtx.com

{triangledown} Published ahead of print on 15 October 2007.

Antimicrobial Agents and Chemotherapy, January 2008, p. 110-120, Vol. 52, No. 1
0066-4804/08/$08.00+0     doi:10.1128/AAC.00863-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Cherwa, J. E. Jr., Sanchez-Soria, P., Members of the University of Arizona Virology Labo, , Wichman, H. A., Fane, B. A. (2009). Viral Adaptation to an Antiviral Protein Enhances the Fitness Level to Above That of the Uninhibited Wild Type. J. Virol. 83: 11746-11750 [Abstract] [Full Text]  
  • Pawlotsky, J.-M. (2009). Review: Therapeutic implications of hepatitis C virus resistance to antiviral drugs. Therapeutic Advances in Gastroenterology 2: 205-219 [Abstract]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»