{"id":343541,"date":"2016-12-29T18:35:35","date_gmt":"2016-12-30T02:35:35","guid":{"rendered":"https:\/\/www.microsoft.com\/en-us\/research\/?post_type=msr-research-item&#038;p=343541"},"modified":"2018-10-16T21:41:15","modified_gmt":"2018-10-17T04:41:15","slug":"hiv-control-single-nucleotide-hla-b-locus","status":"publish","type":"msr-research-item","link":"https:\/\/www.microsoft.com\/en-us\/research\/publication\/hiv-control-single-nucleotide-hla-b-locus\/","title":{"rendered":"HIV Control through a Single Nucleotide on the HLA-B Locus"},"content":{"rendered":"<div id=\"abstract-1\" class=\"section abstract\">\n<p id=\"p-1\">Genetic variation within the HLA-B locus has the strongest impact on HIV disease progression of any polymorphisms within the human genome. However, identifying the exact mechanism involved is complicated by several factors. HLA-Bw4 alleles provide ligands for NK cells and for CD8 T cells, and strong linkage disequilibrium between HLA class I alleles complicates the discrimination of individual HLA allelic effects from those of other HLA and non-HLA alleles on the same haplotype. Here, we exploit an experiment of nature involving two recently diverged HLA alleles, HLA-B*42:01 and HLA-B*42:02, which differ by only a single amino acid. Crucially, they occur primarily on identical HLA class I haplotypes and, as Bw6 alleles, do not act as NK cell ligands and are therefore largely unconfounded by other genetic factors. We show that in an outbred cohort (<em>n<\/em> = 2,093) of HIV C-clade-infected individuals, a single amino acid change at position 9 of the HLA-B molecule critically affects peptide binding and significantly alters the cytotoxic T lymphocyte (CTL) epitopes targeted, measured directly <em>ex vivo<\/em> by gamma interferon (IFN-\u03b3) enzyme-linked immunospot (ELISPOT) assay (<em>P<\/em> = 2 \u00d7 10<sup>\u221210<\/sup>) and functionally through CTL escape mutation (<em>P<\/em> = 2 \u00d7 10<sup>\u22128<\/sup>). HLA-B*42:01, which presents multiple Gag epitopes, is associated with a 0.52 log<sub>10<\/sub>lower viral-load set point than HLA-B*42:02 (<em>P<\/em> = 0.02), which presents no p24 Gag epitopes. The magnitude of this effect from a single amino acid difference in the HLA-A*30:01\/B*42\/Cw*17:01 haplotype is equivalent to 75% of that of HLA-B*57:03, the most protective HLA class I allele in this population. This naturally controlled experiment represents perhaps the clearest demonstration of the direct impact of a particular HIV-specific CTL on disease control.<\/p>\n<\/div>\n","protected":false},"excerpt":{"rendered":"<p>Genetic variation within the HLA-B locus has the strongest impact on HIV disease progression of any polymorphisms within the human genome. However, identifying the exact mechanism involved is complicated by several factors. HLA-Bw4 alleles provide ligands for NK cells and for CD8 T cells, and strong linkage disequilibrium between HLA class I alleles complicates the [&hellip;]<\/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":"","msr-author-ordering":null,"msr_publishername":"","msr_publisher_other":"","msr_booktitle":"","msr_chapter":"","msr_edition":"Journal of Virology","msr_editors":"","msr_how_published":"","msr_isbn":"","msr_issue":"","msr_journal":"Journal of Virology","msr_number":"","msr_organization":"","msr_pages_string":"","msr_page_range_start":"","msr_page_range_end":"","msr_series":"","msr_volume":"","msr_copyright":"","msr_conference_name":"","msr_doi":"10.1128\/JVI.01020-12","msr_arxiv_id":"","msr_s2_paper_id":"","msr_mag_id":"","msr_pubmed_id":"","msr_other_authors":"","msr_other_contributors":"","msr_speaker":"","msr_award":"","msr_affiliation":"","msr_institution":"","msr_host":"","msr_version":"","msr_duration":"","msr_original_fields_of_study":"","msr_release_tracker_id":"","msr_s2_match_type":"","msr_citation_count_updated":"","msr_published_date":"2012-08-15","msr_highlight_text":"","msr_notes":"","msr_longbiography":"","msr_publicationurl":"http:\/\/jvi.asm.org\/content\/86\/21\/11493.abstract?sid=e5fe9a68-e4ff-459d-8679-8d9fc1217606","msr_external_url":"","msr_secondary_video_url":"","msr_conference_url":"","msr_journal_url":"","msr_s2_pdf_url":"","msr_year":0,"msr_citation_count":0,"msr_influential_citations":0,"msr_reference_count":0,"msr_s2_match_confidence":0,"msr_microsoftintellectualproperty":true,"msr_s2_open_access":false,"msr_s2_author_ids":[],"msr_pub_ids":[],"msr_hide_image_in_river":0,"footnotes":""},"msr-research-highlight":[],"research-area":[13553],"msr-publication-type":[193715],"msr-publisher":[],"msr-focus-area":[],"msr-locale":[268875],"msr-post-option":[],"msr-field-of-study":[],"msr-conference":[],"msr-journal":[],"msr-impact-theme":[],"msr-pillar":[],"class_list":["post-343541","msr-research-item","type-msr-research-item","status-publish","hentry","msr-research-area-medical-health-genomics","msr-locale-en_us"],"msr_publishername":"","msr_edition":"Journal of Virology","msr_affiliation":"","msr_published_date":"2012-08-15","msr_host":"","msr_duration":"","msr_version":"","msr_speaker":"","msr_other_contributors":"","msr_booktitle":"","msr_pages_string":"","msr_chapter":"","msr_isbn":"","msr_journal":"Journal of Virology","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:\/\/jvi.asm.org\/content\/86\/21\/11493.abstract?sid=e5fe9a68-e4ff-459d-8679-8d9fc1217606","msr_doi":"10.1128\/JVI.01020-12","msr_publication_uploader":[{"type":"url","title":"http:\/\/jvi.asm.org\/content\/86\/21\/11493.abstract?sid=e5fe9a68-e4ff-459d-8679-8d9fc1217606","viewUrl":false,"id":false,"label_id":0},{"type":"doi","title":"10.1128\/JVI.01020-12","viewUrl":false,"id":false,"label_id":0}],"msr_related_uploader":"","msr_citation_count":0,"msr_citation_count_updated":"","msr_s2_paper_id":"","msr_influential_citations":0,"msr_reference_count":0,"msr_arxiv_id":"","msr_s2_author_ids":[],"msr_s2_open_access":false,"msr_s2_pdf_url":null,"msr_attachments":[{"id":0,"url":"http:\/\/jvi.asm.org\/content\/86\/21\/11493.abstract?sid=e5fe9a68-e4ff-459d-8679-8d9fc1217606"}],"msr-author-ordering":[{"type":"text","value":"Henrik N. 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