{"id":343535,"date":"2016-12-29T18:22:54","date_gmt":"2016-12-30T02:22:54","guid":{"rendered":"https:\/\/www.microsoft.com\/en-us\/research\/?post_type=msr-research-item&p=343535"},"modified":"2018-10-16T21:41:03","modified_gmt":"2018-10-17T04:41:03","slug":"intersubtype-differences-effect-rare-p24-gag-mutation-hiv-1-replicative-fitness","status":"publish","type":"msr-research-item","link":"https:\/\/www.microsoft.com\/en-us\/research\/publication\/intersubtype-differences-effect-rare-p24-gag-mutation-hiv-1-replicative-fitness\/","title":{"rendered":"Intersubtype differences in the effect of a rare p24 Gag mutation on HIV-1 replicative fitness"},"content":{"rendered":"
\n

Certain immune-driven mutations in HIV-1, such as those arising in p24Gag<\/sup>, decrease viral replicative capacity. However, inter-subtype differences in the replicative consequences of such mutations have not been explored. In HIV-1 subtype B, the p24Gag<\/sup> M250I mutation is a rare variant (0.6%) that is enriched among elite controllers (7.2%) (p=0.0005) and appears to be a rare escape variant selected by HLA-B58 supertype alleles (p<0.01). By contrast, in subtype C, it is a relatively common minor polymorphic variant (10-15%) whose appearance is not associated with a particular HLA allele. Using site-directed mutant viruses, we demonstrate that M250I reduces in vitro<\/em> viral replicative capacity in both subtype B and subtype C sequences. However, whereas in subtype C downstream compensatory mutations at p24Gag<\/sup> codons 252 and 260 reduce the adverse effects of M250I, fitness costs in subtype B appear difficult to restore. Indeed, patient-derived subtype B sequences harboring M250I exhibited in vitro<\/em> replicative defects while those from subtype C did not. The structural implications of M250I were predicted by protein modeling to be greater in subtype B versus C, providing a potential explanation for its lower frequency and enhanced replicative defects in subtype B. In addition to accounting for genetic differences between HIV-1 subtypes, the design of CTL-based vaccines may need to account for differential effects of host-driven viral evolution on viral fitness.<\/p>\n<\/div>\n","protected":false},"excerpt":{"rendered":"

Certain immune-driven mutations in HIV-1, such as those arising in p24Gag, decrease viral replicative capacity. However, inter-subtype differences in the replicative consequences of such mutations have not been explored. In HIV-1 subtype B, the p24Gag M250I mutation is a rare variant (0.6%) that is enriched among elite controllers (7.2%) (p=0.0005) and appears to be a […]<\/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.02171-12","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":"2012-09-26","msr_highlight_text":"","msr_notes":"","msr_longbiography":"","msr_publicationurl":"http:\/\/jvi.asm.org\/content\/early\/2012\/09\/20\/JVI.02171-12.short","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-343535","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":"2012-09-26","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\/early\/2012\/09\/20\/JVI.02171-12.short","msr_doi":"10.1128\/JVI.02171-12","msr_publication_uploader":[{"type":"url","title":"http:\/\/jvi.asm.org\/content\/early\/2012\/09\/20\/JVI.02171-12.short","viewUrl":false,"id":false,"label_id":0},{"type":"doi","title":"10.1128\/JVI.02171-12","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\/early\/2012\/09\/20\/JVI.02171-12.short"}],"msr-author-ordering":[{"type":"text","value":"Denis R. 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