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Journal of Virology, February 2007, p. 2031-2038, Vol. 81, No. 4
0022-538X/07/$08.00+0     doi:10.1128/JVI.00968-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Precise Identification of a Human Immunodeficiency Virus Type 1 Antigen Processing Mutant{triangledown}

Peter Zimbwa,1,{dagger} Anita Milicic,1,{dagger}* John Frater,1 Thomas J. Scriba,1 Antony Willis,2 Philip J. R. Goulder,3 Tilly Pillay,1 Huldrych Gunthard,4 Jonathan N. Weber,5 Hua-Tang Zhang,1 and Rodney E. Phillips1

The James Martin 21st Century School at The Peter Medawar Building for Pathogen Research, Nuffield Department of Clinical Medicine, University of Oxford, South Parks Road, Oxford OX1 3SY, United Kingdom,1 Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, United Kingdom,2 Department of Pediatrics, University of Oxford, Oxford OX3 9DU, United Kingdom,3 University Hospital Zurich, Department of Medicine, Division of Infectious Diseases and Hospital Epidemiology, Ramistrasse 100, CH-8091 Zurich, Switzerland,4 Jefferiss Research Laboratories, Wright-Fleming Institute, Imperial College, St Mary's Hospital, Norfolk Place, London W2 1PG, United Kingdom5

Received 11 May 2006/ Accepted 9 November 2006

Human immunodeficiency virus type 1 (HIV-1) evokes a strong immune response, but the virus persists. Polymorphisms within known antigenic sites result in loss of immune recognition and can be positively selected. Amino acid variation outside known HLA class I restricted epitopes can also enable immune escape by interfering with the processing of the optimal peptide antigen. However, the lack of precise rules dictating epitope generation and the enormous genetic diversity of HIV make prediction of processing mutants very difficult. Polymorphism E169D in HIV-1 reverse transcriptase (RT) is significantly associated with HLA-B*0702 in HIV-1-infected individuals. This polymorphism does not map within a known HLA-B*0702 epitope; instead, it is located five residues downstream of a HLA-B*0702-restricted epitope SPAIFQSSM (SM9). Here we investigate the association between E169D and HLA-B*0702 for immune escape via the SM9 epitope. We show that this single amino acid variation prevents the immune recognition of the flanked SM9 epitope by cytotoxic T cells through lack of generation of the epitope, which is a result of aberrant proteasomal cleavage. The E169D polymorphism also maps within and abrogates the recognition of an HLA-A*03-restricted RT epitope MR9. This study highlights the potential for using known statistical associations as indicators for viral escape but also the complexity involved in interpreting the immunological consequences of amino acid changes in HIV sequences.

* Corresponding author. Mailing address: The James Martin 21st Century School at The Peter Medawar Building for Pathogen Research, Nuffield Department of Clinical Medicine, University of Oxford, South Parks Road, Oxford OX1 3SY, United Kingdom. Phone: 44 794 1969 255. Fax: 44 1865 617028. E-mail: anita.milicic{at}clinpharm.ox.ac.uk.

{triangledown} Published ahead of print on 15 November 2006.

{dagger} P.Z. and A.M. contributed equally to this study.

Journal of Virology, February 2007, p. 2031-2038, Vol. 81, No. 4
0022-538X/07/$08.00+0     doi:10.1128/JVI.00968-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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