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Journal of Virology, September 2006, p. 8695-8704, Vol. 80, No. 17
0022-538X/06/$08.00+0     doi:10.1128/JVI.00271-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Identification of Conserved Residues in the E2 Envelope Glycoprotein of the Hepatitis C Virus That Are Critical for CD81 Binding

Ania M. Owsianka,1,{dagger} Judith M. Timms,2,{dagger} Alexander W. Tarr,2 Richard J. P. Brown,2 Timothy P. Hickling,2 Aleksandra Szwejk,1,3 Krystyna Bienkowska-Szewczyk,3 Brian J. Thomson,2 Arvind H. Patel,1* and Jonathan K. Ball2*

MRC Virology Unit, Institute of Virology, University of Glasgow, Church Street, Glasgow G11 5JR, United Kingdom,1 Institute of Infection, Immunity and Inflammation, School of Molecular Medical Sciences, The University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, United Kingdom,2 Department of Molecular Virology, University of Gdansk, Kladki 24, 80-822 Gdansk, Poland3

Received 7 February 2006/ Accepted 31 May 2006

Hepatitis C virus (HCV) cell entry involves interaction between the viral envelope glycoprotein E2 and the cell surface receptor CD81. Knowledge of conserved E2 determinants important for successful binding will facilitate development of entry inhibitors designed to block this interaction. Previous studies have assigned the CD81 binding function to a number of discontinuous regions of E2. To better define specific residues involved in receptor binding, a panel of mutants of HCV envelope proteins was generated, where conserved residues within putative CD81 binding regions were sequentially mutated to alanine. Mutant proteins were tested for binding to a panel of monoclonal antibodies and CD81 and for their ability to form noncovalent heterodimers and confer infectivity in the retroviral pseudoparticle (HCVpp) assay. Detection by conformation-sensitive monoclonal antibodies indicated that the mutant proteins were correctly folded. Mutant proteins fell into three groups: those that bound CD81 and conferred HCVpp infectivity, those that abrogated both CD81 binding and HCVpp infectivity, and a final group containing mutants that were able to bind CD81 but were noninfectious in the HCVpp assay. Specific amino acids conserved across all genotypes that were critical for CD81 binding were W420, Y527, W529, G530, and D535. These data significantly increase our understanding of the CD81 receptor-E2 binding process.

* Corresponding author. Mailing address for Jonathan K. Ball: Institute of Infection, Immunity and Inflammation, School of Molecular Medical Sciences, The University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, United Kingdom. Phone: 44 115 970 9162. Fax: 44 115 970 9233. E-mail: jonathan.ball{at}nottingham.ac.uk. Mailing address for Arvind H. Patel: MRC Virology Unit, Institute of Virology, University of Glasgow, Church Street, Glasgow G11 5JR, United Kingdom. Phone: 44 141 330 4026. Fax: 44 141 337 2236. E-mail: a.patel{at}vir.gla.ac.uk.

{dagger} These authors contributed equally.

Journal of Virology, September 2006, p. 8695-8704, Vol. 80, No. 17
0022-538X/06/$08.00+0     doi:10.1128/JVI.00271-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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