Background<\/p>\n
HLA class I genotype is a major determinant of the outcome of HIV infection, and the impact of certain alleles on HIV disease outcome is well studied. Recent studies have demonstrated that certain HLA class I alleles that are in linkage disequilibrium, such as HLA-A*74 and HLA-B*57, appear to function co-operatively to result in greater immune control of HIV than mediated by either single allele alone. We here investigate the extent to which HLA alleles – irrespective of linkage disequilibrium – function co-operatively.<\/p>\n
Methodology\/Principal Findings<\/p>\n
We here refined a computational approach to the analysis of >2000 subjects infected with C-clade HIV first to discern the individual effect of each allele on disease control, and second to identify pairs of alleles that mediate \u2018co-operative additive\u2019 effects, either to improve disease suppression or to contribute to immunological failure. We identified six pairs of HLA class I alleles that have a co-operative additive effect in mediating HIV disease control and four hazardous pairs of alleles that, occurring together, are predictive of worse disease outcomes (q<0.05 in each case). We developed a novel \u2018sharing score\u2019 to quantify the breadth of CD8+ T cell responses made by pairs of HLA alleles across the HIV proteome, and used this to demonstrate that successful viraemic suppression correlates with breadth of unique CD8+ T cell responses (p\u200a=\u200a0.03).\n\nConclusions\/Significance\n\nThese results identify co-operative effects between HLA Class I alleles in the control of HIV-1 in an extended Southern African cohort, and underline complementarity and breadth of the CD8+ T cell targeting as one potential mechanism for this effect.\n\n<\/p>\n","protected":false},"excerpt":{"rendered":"
Background HLA class I genotype is a major determinant of the outcome of HIV infection, and the impact of certain alleles on HIV disease outcome is well studied. Recent studies have demonstrated that certain HLA class I alleles that are in linkage disequilibrium, such as HLA-A*74 and HLA-B*57, appear to function co-operatively to result in […]<\/p>\n","protected":false},"featured_media":0,"template":"","meta":{"msr-url-field":"","msr-podcast-episode":"","msrModifiedDate":"","msrModifiedDateEnabled":false,"ep_exclude_from_search":false,"_classifai_error":"","footnotes":""},"msr-content-type":[3],"msr-research-highlight":[],"research-area":[13553],"msr-publication-type":[193715],"msr-product-type":[],"msr-focus-area":[],"msr-platform":[],"msr-download-source":[],"msr-locale":[268875],"msr-post-option":[],"msr-field-of-study":[],"msr-conference":[],"msr-journal":[],"msr-impact-theme":[],"msr-pillar":[],"class_list":["post-322961","msr-research-item","type-msr-research-item","status-publish","hentry","msr-research-area-medical-health-genomics","msr-locale-en_us"],"msr_publishername":"","msr_edition":"","msr_affiliation":"","msr_published_date":"2012-10-19","msr_host":"","msr_duration":"","msr_version":"","msr_speaker":"","msr_other_contributors":"","msr_booktitle":"","msr_pages_string":"e47799","msr_chapter":"","msr_isbn":"","msr_journal":"PLoS ONE","msr_volume":"","msr_number":"","msr_editors":"","msr_series":"","msr_issue":"","msr_organization":"","msr_how_published":"","msr_notes":"","msr_highlight_text":"","msr_release_tracker_id":"","msr_original_fields_of_study":"","msr_download_urls":"","msr_external_url":"","msr_secondary_video_url":"","msr_longbiography":"","msr_microsoftintellectualproperty":1,"msr_main_download":"","msr_publicationurl":"http:\/\/journals.plos.org\/plosone\/article?id=10.1371\/journal.pone.0047799","msr_doi":"10.1371\/journal.pone.0047799","msr_publication_uploader":[{"type":"url","title":"http:\/\/journals.plos.org\/plosone\/article?id=10.1371\/journal.pone.0047799","viewUrl":false,"id":false,"label_id":0},{"type":"doi","title":"10.1371\/journal.pone.0047799","viewUrl":false,"id":false,"label_id":0}],"msr_related_uploader":"","msr_attachments":[{"id":0,"url":"http:\/\/journals.plos.org\/plosone\/article?id=10.1371\/journal.pone.0047799"}],"msr-author-ordering":[{"type":"text","value":"Philippa C. 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