{"id":315701,"date":"2016-11-03T19:48:26","date_gmt":"2016-11-04T02:48:26","guid":{"rendered":"https:\/\/www.microsoft.com\/en-us\/research\/?post_type=msr-research-item&#038;p=315701"},"modified":"2018-10-16T20:07:08","modified_gmt":"2018-10-17T03:07:08","slug":"reduced-replication-capacity-nl4-3-recombinant-viruses-encoding-reverse-transcriptase-integrase-sequences-hiv-1-elite-controllers","status":"publish","type":"msr-research-item","link":"https:\/\/www.microsoft.com\/en-us\/research\/publication\/reduced-replication-capacity-nl4-3-recombinant-viruses-encoding-reverse-transcriptase-integrase-sequences-hiv-1-elite-controllers\/","title":{"rendered":"Reduced Replication Capacity of NL4-3 Recombinant Viruses Encoding Reverse Transcriptase Integrase Sequences From HIV-1 Elite Controllers"},"content":{"rendered":"<div id=\"S1\" class=\"sec sec-first\">\n<h3>Background<\/h3>\n<p id=\"P2\" class=\"p p-first-last\">Identifying viral and host determinants of HIV-1 elite control may help inform novel therapeutic and\/or vaccination strategies. Previously, we observed decreased replication capacity in controller-derived viruses suggesting that fitness consequences of HLA class I-associated escape mutations in Gag may contribute to this phenotype. This study examines whether similar functional defects occur in Pol proteins of elite controllers.<\/p>\n<\/div>\n<div id=\"S2\" class=\"sec\">\n<h3>Methods<\/h3>\n<p id=\"P3\" class=\"p p-first-last\">Recombinant NL4-3 viruses encoding plasma RNA-derived Reverse Transcriptase (RT)-Integrase sequences from 58 elite controllers and 50 untreated chronic progressors were constructed and replication capacity measured in vitro using a GFP reporter T-cell assay. Sequences were analyzed for drug resistance and HLA-associated viral polymorphisms.<\/p>\n<\/div>\n<div id=\"S3\" class=\"sec\">\n<h3>Results<\/h3>\n<p id=\"P4\" class=\"p p-first-last\">Controller-derived viruses displayed significantly lower replication capacity compared to those from progressors (p<0.0001). Among controllers, the most attenuated viruses were generated from individuals expressing HLA-B*57 or B*51. In viruses from B*57+ progressors (N=8), a significant inverse correlation was observed between B*57-associated RT-Integrase escape mutations and replication capacity (R=\u22120.89; p=0.003); a similar trend was observed in B*57+ controller-derived viruses (N=20, R=\u22120.36; p=0.08).<\/p>\n<\/div>\n<div id=\"S4\" class=\"sec sec-last\">\n<h3>Conclusions<\/h3>\n<p id=\"P5\" class=\"p p-first-last\">HIV-1 Pol function appeared to be compromised in elite controllers. As observed previously for Gag, HLA-associated immune pressure in Pol may contribute to viral attenuation and subsequent control of viremia.<\/p>\n<\/div>\n","protected":false},"excerpt":{"rendered":"<p>Background Identifying viral and host determinants of HIV-1 elite control may help inform novel therapeutic and\/or vaccination strategies. Previously, we observed decreased replication capacity in controller-derived viruses suggesting that fitness consequences of HLA class I-associated escape mutations in Gag may contribute to this phenotype. This study examines whether similar functional defects occur in Pol proteins [&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":"J Acquir Immune Defic Syndr.","msr_editors":"","msr_how_published":"","msr_isbn":"","msr_issue":"","msr_journal":"J Acquir Immune Defic Syndr.","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":"10.1097\/QAI.0b013e3181fe9450","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":"2011-02-01","msr_highlight_text":"","msr_notes":"","msr_longbiography":"","msr_publicationurl":"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC3078702\/?tool=pubmed","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-315701","msr-research-item","type-msr-research-item","status-publish","hentry","msr-research-area-medical-health-genomics","msr-locale-en_us"],"msr_publishername":"","msr_edition":"J Acquir Immune Defic Syndr.","msr_affiliation":"","msr_published_date":"2011-02-01","msr_host":"","msr_duration":"","msr_version":"","msr_speaker":"","msr_other_contributors":"","msr_booktitle":"","msr_pages_string":"","msr_chapter":"","msr_isbn":"","msr_journal":"J Acquir Immune Defic Syndr.","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":"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC3078702\/?tool=pubmed","msr_doi":"10.1097\/QAI.0b013e3181fe9450","msr_publication_uploader":[{"type":"url","title":"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC3078702\/?tool=pubmed","viewUrl":false,"id":false,"label_id":0},{"type":"doi","title":"10.1097\/QAI.0b013e3181fe9450","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":"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC3078702\/?tool=pubmed"}],"msr-author-ordering":[{"type":"text","value":"Zabrina L. 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