title: Precise identification of a human immunodeficiency virus type 1 antigen processing mutant.
abstract: 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.
authors.affiliation: 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.
authors.forename: Peter
authors.initials: P
authors.lastname: Zimbwa
authors.forename: Anita
authors.initials: A
authors.lastname: Milicic
authors.forename: John
authors.initials: J
authors.lastname: Frater
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Scriba
authors.forename: Antony
authors.initials: A
authors.lastname: Willis
authors.forename: Philip J R
authors.initials: PJ
authors.lastname: Goulder
authors.forename: Tilly
authors.initials: T
authors.lastname: Pillay
authors.forename: Huldrych
authors.initials: H
authors.lastname: Gunthard
authors.forename: Jonathan N
authors.initials: JN
authors.lastname: Weber
authors.forename: Hua-Tang
authors.initials: HT
authors.lastname: Zhang
authors.forename: Rodney E
authors.initials: RE
authors.lastname: Phillips
mesh_terms: D000595:Amino Acid Sequence; D000956:Antigens, Viral / Q000235:genetics* / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000235:genetics* / Q000276:immunology; D005838:Genotype; D015658:HIV Infections / Q000235:genetics / Q000276:immunology*; D054303:HIV Reverse Transcriptase / Q000235:genetics* / Q000276:immunology; D015497:HIV-1 / Q000276:immunology*; D015235:HLA-B Antigens / Q000235:genetics; D006801:Humans; D007963:Leukocytes, Mononuclear; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D011110:Polymorphism, Genetic; D013045:Species Specificity; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
chemical_list: D000956:Antigens, Viral; D018984:Epitopes, T-Lymphocyte; D015235:HLA-B Antigens; D054303:HIV Reverse Transcriptase