title: Interdisciplinary analysis of HIV-specific CD8+ T cell responses against variant epitopes reveals restricted TCR promiscuity.
abstract: HIV-1-specific CTL responses play a key role in limiting viral replication. CTL responses are sensitive to viral escape mutations, which influence recognition of the virus. Although CTLs have been shown to recognize epitope variants, the extent of this cross-reactivity has not been quantitatively investigated in a genetically diverse cohort of HIV-1-infected patients. Using a novel bioinformatic binding prediction method, we aimed to explain the pattern of epitope-specific CTL responses based on the patients' HLA genotype and autologous virus sequence quantitatively. Sequences covering predicted and tested HLA class I-restricted epitopes (peptides) within the HIV-Gag, Pol, and Nef regions were obtained from 26 study subjects resulting in 1492 patient-specific peptide pairs. Epitopes that were recognized in ELISPOT assays were found to be significantly more similar to the autologous virus than those that did not elicit a response. A single substitution in the presented epitope decreased the chance of a CTL response by 40%. The impact of sequence similarity on cross-recognition was confirmed by testing immune responses against multiple variants of six selected epitopes. Substitutions at central positions in the epitope were particularly likely to result in abrogation of recognition. In summary, the presented data demonstrate a highly restricted promiscuity of HIV-1-specific CTL in the recognition of variant epitopes. In addition, our results illustrate that bioinformatic prediction methods are useful to study the complex pattern of CTL responses exhibited by an HIV-1-infected patient cohort and for identification of optimal targets for novel therapeutic or vaccine approaches.
authors.affiliation: Department of Systems Biology, Center for Biological Sequence Analysis, Technical University of Denmark, Lyngby, Denmark.
authors.forename: Ilka
authors.initials: I
authors.lastname: Hoof
authors.forename: Carina L
authors.initials: CL
authors.lastname: Pérez
authors.forename: Marcus
authors.initials: M
authors.lastname: Buggert
authors.forename: Rasmus K L
authors.initials: RK
authors.lastname: Gustafsson
authors.forename: Morten
authors.initials: M
authors.lastname: Nielsen
authors.forename: Ole
authors.initials: O
authors.lastname: Lund
authors.forename: Annika C
authors.initials: AC
authors.lastname: Karlsson
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D005260:Female; D015497:HIV-1 / Q000276:immunology*; D015234:HLA-A Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015789:HLA-A2 Antigen / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015235:HLA-B Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D059948:HLA-B44 Antigen; D015793:HLA-B7 Antigen; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D011237:Predictive Value of Tests; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D018984:Epitopes, T-Lymphocyte; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D015235:HLA-B Antigens; C477444:HLA-B*07:02 antigen; D059948:HLA-B44 Antigen; D015793:HLA-B7 Antigen; D015395:Histocompatibility Antigens Class I; D011948:Receptors, Antigen, T-Cell