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 Google Scholar
Google Scholar
Right arrow Articles by Prado, J. G.
Right arrow Articles by Goulder, P. J. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Prado, J. G.
Right arrow Articles by Goulder, P. J. R.

 Previous Article  |  Next Article 

Journal of Virology, January 2009, p. 1018-1025, Vol. 83, No. 2
0022-538X/09/$08.00+0     doi:10.1128/JVI.01882-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Functional Consequences of Human Immunodeficiency Virus Escape from an HLA-B*13-Restricted CD8+ T-Cell Epitope in p1 Gag Protein{triangledown}

Julia G. Prado,1 Isobella Honeyborne,1 Ian Brierley,2 Maria Carmen Puertas,3 Javier Martinez-Picado,3,4 and Philip J. R. Goulder1,5,6*

Department of Paediatrics, University of Oxford, Peter Medawar Building for Pathogen Research, South Parks Rd., Oxford OX1 3SY, United Kingdom,1 Division of Virology, Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, United Kingdom,2 Fundació IrsiCaixa, Hospital Universitari Germans Trias i Pujol, Badalona, Spain,3 Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain,4 HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban 4013, South Africa,5 Partners AIDS Research Center, Massachusetts General Hospital, 13th St., Bldg. 149, Charlestown, Boston, Massachusetts 021296

Received 8 September 2008/ Accepted 13 October 2008

The observed association between HLA-B*13 and control of human immunodeficiency virus type 1 (HIV-1) infection has been linked to the number of Gag-specific HLA-B*13-restricted cytotoxic T-cell (CTL) responses identified. To date, the Gag escape mutations described that result in an in vitro fitness cost to the virus have been located within structural protein p24 only. Here we investigated the hypothesis that CTL escape mutations within other regions of HIV Gag may also reduce viral fitness and contribute to immune control. We analyzed an HLA-B*13-restricted CTL response toward an epitope in p1 Gag, RQANFLGKI429-437 (RI9), where amino acid variation at Gag residues 436 and 437 is associated with HLA-B*13 expression. In this work, we assessed the impact of amino acid substitutions at these positions on CTL recognition and on HIV-1 fitness. We demonstrated that substitutions I437L and I437M largely abrogate CTL recognition and reduce viral fitness while variants K436R and I437V have only a marginal effect on recognition and fitness. Examination of the patterns of protein synthesis indicated that the loss of fitness in the I437L and I437M mutants is associated with the accumulation of unprocessed Gag precursors. A significant reduction in ribosomal frameshifting efficiency was observed with I437M, suggesting that this mechanism contributes to the observed reduced fitness of this virus. These studies illustrate the apparent trade-off available to the virus between evasion of CTL recognition in p1 Gag and the functional consequences for viral fitness.

* Corresponding author. Mailing address: Department of Paediatrics, University of Oxford, Peter Medawar Building for Pathogen Research, South Parks Rd., Oxford OX1 3SY, United Kingdom. Phone: 44 1865 281884. Fax: 44 1865 281236. E-mail: philip.goulder{at}paediatrics.ox.ac.uk

{triangledown} Published ahead of print on 22 October 2008.

Journal of Virology, January 2009, p. 1018-1025, Vol. 83, No. 2
0022-538X/09/$08.00+0     doi:10.1128/JVI.01882-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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