{"id":41530,"date":"2023-07-21T00:00:29","date_gmt":"2023-07-21T07:00:29","guid":{"rendered":"https:\/\/vermont.salk.edu\/?post_type=disclosure&p=41530"},"modified":"2023-12-08T20:18:49","modified_gmt":"2023-12-09T04:18:49","slug":"revealing-hiv-drug-resistance-mechanisms-through-protein-structures","status":"publish","type":"disclosure","link":"https:\/\/www.salk.edu\/de\/news-release\/revealing-hiv-drug-resistance-mechanisms-through-protein-structures\/","title":{"rendered":"Revealing HIV drug-resistance mechanisms through protein structures"},"content":{"rendered":"

LA JOLLA\u2014Salk Institute researchers, in collaboration with the National Institutes of Health, have discovered the molecular mechanisms by which the human immunodeficiency virus (HIV) becomes resistant to Dolutegravir, one of the most effective, clinically used antiviral drugs for treating HIV.<\/p>\n

The new study, published July 21, 2023 in Science Advances<\/em><\/a>, reveals how changes to the 3D structures of integrase, an HIV protein, can lead to Dolutegravir resistance and how other compounds may be able to overcome this resistance.<\/p>\n

\u201cWith HIV, one must think two steps ahead of the virus,\u201d says Salk Associate Professor Dmitri Lyumkis<\/a>, co-senior author and the Hearst Foundation Developmental Chair. \u201cWe\u2019ve now determined how the virus could continue evolving against drugs like Dolutegravir, which is important to consider for the development of future therapeutics.\u201d<\/p>\n

\"From
From left: Tim Strutzenberg, Zelin Shan, Dmitry Lyumkis, Dario Passos, and Avik Biswas.
Klicken Sie hier<\/a> f\u00fcr ein hochaufl\u00f6sendes Bild.
Kredit: Salk Institut<\/figcaption><\/figure>\n

HIV infection depends on the ability of the virus to paste its own genetic material into the genomes of human cells, essentially hijacking the cells to become virus-producing factories. Dolutegravir and related drugs work by blocking integrase, a protein critical to the ability of the virus to integrate its own DNA into the host genome. Without functioning integrase, HIV can\u2019t effectively infect human cells. However, HIV is a rapidly mutating virus, and an increasing number of HIV strains are resistant to Dolutegravir.<\/p>\n

In the past, Lyumkis\u2019 lab discovered the 3D structure of the integrase protein while attached to DNA<\/a> as well as exactly how drugs like Dolutegravir bind to and block integrase<\/a>. But researchers weren\u2019t sure how the integrase structure changed when the virus stopped responding to Dolutegravir.<\/p>\n

In the new study, Lyumkis and collaborators from the National Institutes of Health created versions of the integrase protein with mutations known to make HIV resistant to Dolutegravir. Then they determined the structure of each mutant integrase, revealing why Dolutegravir could no longer bind to and block each version of the protein. The scientists also evaluated the \u201cfitness\u201d of the virus (its capacity to produce infectious descendants) and the activity of the enzyme to better understand what leads to drug resistance in patients.<\/p>\n

\u201cWe were quite surprised by the magnitude of resistance that these integrase variants had,\u201d says Lyumkis. \u201cThe ability of Dolutegravir to function was completely compromised.\u201d<\/p>\n

The researchers also tested the efficacy of an experimental HIV drug, 4d, to block the function of Dolutegravir-resistant integrase proteins. 4d was developed by Lyumkis\u2019 collaborators at the NIH as a next-generation integrase-targeting drug and is currently in pre-clinical animal trials. In all the variants, they discovered that 4d still potently blocked the ability of HIV to integrate its genes into human cells. This suggests that 4d, or variants of this compound, may be effectively used to treat the virus in patients who have developed resistance to Dolutegravir.<\/p>\n

The structural data on how 4d binds to the Dolutegravir-resistant integrase proteins also hinted at how new drugs could overcome drug resistance.<\/p>\n

\u201c4d is really just an example of how to combat drug resistance, but it provides us with some basic principles that we can learn from to design other therapeutics,\u201d says co-senior author Robert Craigie of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), part of the National Institutes of Health. \u201cThe way a section of the 4d molecule stacks like a flat sheet on top of a section of the integrase protein-DNA assembly could be replicated in other compounds.\u201d<\/p>\n

Next, the scientists will study how integrase variants evolve\u2014including those not yet seen in patients but possible in the future\u2014and how they impact response to the best clinically used drugs as well as the ability of HIV to infect humans.<\/p>\n

Other authors include Dario Oliveira Passos, Zelin Shan, Avik Biswas and Timothy S. Strutzenberg of Salk; Min Li, Zhaoyang Li, Steven J. Smith, Xue Zhi Zhao, Terrence R. Burke, Jr. and Stephen H. Hughes of the National Institutes of Health; Qinfang Sun, Indrani Choudhuri, Allan Haldane, and Ronald M. Levy of Temple University; Nanjie Deng of Pace University; and Lorenzo Briganti and Mamuka Kvaratskhelia of University of Colorado Anschutz Medical Campus.<\/p>\n

The work was supported by the National Institutes of Health (U01 AI136680, R01 AI146017, U54 AI170855, R35 GM132090), the NIDDK Intramural Program, the Margaret T. Morris Foundation, the Hearst Foundation, the NIH Intramural Program, the Center for Cancer Research, the National Cancer Institute, the NIH AIDS Intramural Targeted Program, and an F32 Postdoctoral Fellowship (GM148049).<\/p>\n

The content in this release is the sole responsibility of the authors and does not necessarily represent the official views or imply endorsement of the National Institutes of Health.<\/p>","protected":false},"featured_media":0,"template":"","faculty":[320],"disease-research":[449,333,122,366],"class_list":["post-41530","disclosure","type-disclosure","status-publish","hentry","faculty-dmitry-lyumkis","disease-research-biochemistry-and-biophysics","disease-research-genetics","disease-research-immune-system-biology","disease-research-infectious-disease"],"acf":[],"yoast_head":"\nRevealing HIV drug-resistance mechanisms through protein structures - Salk Institute for Biological Studies<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/www.salk.edu\/de\/news-release\/revealing-hiv-drug-resistance-mechanisms-through-protein-structures\/\" \/>\n<meta property=\"og:locale\" content=\"de_DE\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Revealing HIV drug-resistance mechanisms through protein structures - Salk Institute for Biological Studies\" \/>\n<meta property=\"og:description\" content=\"LA JOLLA\u2014Salk Institute researchers, in collaboration with the National Institutes of Health, have discovered the molecular mechanisms by which the human immunodeficiency virus (HIV) becomes resistant to Dolutegravir, one of the most effective, clinically used antiviral drugs for treating HIV.\" \/>\n<meta property=\"og:url\" content=\"https:\/\/www.salk.edu\/de\/news-release\/revealing-hiv-drug-resistance-mechanisms-through-protein-structures\/\" \/>\n<meta property=\"og:site_name\" content=\"Salk Institute for Biological Studies\" \/>\n<meta property=\"article:modified_time\" content=\"2023-12-09T04:18:49+00:00\" \/>\n<meta property=\"og:image\" content=\"http:\/\/www.salk.edu\/wp-content\/uploads\/2023\/07\/Lyumkis-PR-20230706-551A3434-458x305.jpg\" \/>\n<meta name=\"twitter:card\" content=\"summary_large_image\" \/>\n<meta name=\"twitter:label1\" content=\"Est. reading time\" \/>\n\t<meta name=\"twitter:data1\" content=\"4 minutes\" \/>\n<script type=\"application\/ld+json\" class=\"yoast-schema-graph\">{\"@context\":\"https:\\\/\\\/schema.org\",\"@graph\":[{\"@type\":\"WebPage\",\"@id\":\"https:\\\/\\\/www.salk.edu\\\/news-release\\\/revealing-hiv-drug-resistance-mechanisms-through-protein-structures\\\/\",\"url\":\"https:\\\/\\\/www.salk.edu\\\/news-release\\\/revealing-hiv-drug-resistance-mechanisms-through-protein-structures\\\/\",\"name\":\"Revealing HIV drug-resistance mechanisms through protein structures - Salk Institute for Biological Studies\",\"isPartOf\":{\"@id\":\"https:\\\/\\\/www.salk.edu\\\/#website\"},\"primaryImageOfPage\":{\"@id\":\"https:\\\/\\\/www.salk.edu\\\/news-release\\\/revealing-hiv-drug-resistance-mechanisms-through-protein-structures\\\/#primaryimage\"},\"image\":{\"@id\":\"https:\\\/\\\/www.salk.edu\\\/news-release\\\/revealing-hiv-drug-resistance-mechanisms-through-protein-structures\\\/#primaryimage\"},\"thumbnailUrl\":\"http:\\\/\\\/www.salk.edu\\\/wp-content\\\/uploads\\\/2023\\\/07\\\/Lyumkis-PR-20230706-551A3434-458x305.jpg\",\"datePublished\":\"2023-07-21T07:00:29+00:00\",\"dateModified\":\"2023-12-09T04:18:49+00:00\",\"breadcrumb\":{\"@id\":\"https:\\\/\\\/www.salk.edu\\\/news-release\\\/revealing-hiv-drug-resistance-mechanisms-through-protein-structures\\\/#breadcrumb\"},\"inLanguage\":\"de-DE\",\"potentialAction\":[{\"@type\":\"ReadAction\",\"target\":[\"https:\\\/\\\/www.salk.edu\\\/news-release\\\/revealing-hiv-drug-resistance-mechanisms-through-protein-structures\\\/\"]}]},{\"@type\":\"ImageObject\",\"inLanguage\":\"de-DE\",\"@id\":\"https:\\\/\\\/www.salk.edu\\\/news-release\\\/revealing-hiv-drug-resistance-mechanisms-through-protein-structures\\\/#primaryimage\",\"url\":\"http:\\\/\\\/www.salk.edu\\\/wp-content\\\/uploads\\\/2023\\\/07\\\/Lyumkis-PR-20230706-551A3434-458x305.jpg\",\"contentUrl\":\"http:\\\/\\\/www.salk.edu\\\/wp-content\\\/uploads\\\/2023\\\/07\\\/Lyumkis-PR-20230706-551A3434-458x305.jpg\"},{\"@type\":\"BreadcrumbList\",\"@id\":\"https:\\\/\\\/www.salk.edu\\\/news-release\\\/revealing-hiv-drug-resistance-mechanisms-through-protein-structures\\\/#breadcrumb\",\"itemListElement\":[{\"@type\":\"ListItem\",\"position\":1,\"name\":\"Home\",\"item\":\"https:\\\/\\\/www.salk.edu\\\/\"},{\"@type\":\"ListItem\",\"position\":2,\"name\":\"Revealing HIV drug-resistance mechanisms through protein structures\"}]},{\"@type\":\"WebSite\",\"@id\":\"https:\\\/\\\/www.salk.edu\\\/#website\",\"url\":\"https:\\\/\\\/www.salk.edu\\\/\",\"name\":\"Salk Institute for Biological Studies\",\"description\":\"The Power of Science\",\"publisher\":{\"@id\":\"https:\\\/\\\/www.salk.edu\\\/#organization\"},\"potentialAction\":[{\"@type\":\"SearchAction\",\"target\":{\"@type\":\"EntryPoint\",\"urlTemplate\":\"https:\\\/\\\/www.salk.edu\\\/?s={search_term_string}\"},\"query-input\":{\"@type\":\"PropertyValueSpecification\",\"valueRequired\":true,\"valueName\":\"search_term_string\"}}],\"inLanguage\":\"de-DE\"},{\"@type\":\"Organization\",\"@id\":\"https:\\\/\\\/www.salk.edu\\\/#organization\",\"name\":\"Salk Institute for Biological Studies\",\"url\":\"https:\\\/\\\/www.salk.edu\\\/\",\"logo\":{\"@type\":\"ImageObject\",\"inLanguage\":\"de-DE\",\"@id\":\"https:\\\/\\\/www.salk.edu\\\/#\\\/schema\\\/logo\\\/image\\\/\",\"url\":\"http:\\\/\\\/www.salk.edu\\\/wp-content\\\/uploads\\\/2023\\\/03\\\/salk_logo_696.jpg\",\"contentUrl\":\"http:\\\/\\\/www.salk.edu\\\/wp-content\\\/uploads\\\/2023\\\/03\\\/salk_logo_696.jpg\",\"width\":696,\"height\":696,\"caption\":\"Salk Institute for Biological Studies\"},\"image\":{\"@id\":\"https:\\\/\\\/www.salk.edu\\\/#\\\/schema\\\/logo\\\/image\\\/\"}}]}<\/script>\n<!-- \/ Yoast SEO plugin. -->","yoast_head_json":{"title":"Revealing HIV drug-resistance mechanisms through protein structures - Salk Institute for Biological Studies","robots":{"index":"index","follow":"follow","max-snippet":"max-snippet:-1","max-image-preview":"max-image-preview:large","max-video-preview":"max-video-preview:-1"},"canonical":"https:\/\/www.salk.edu\/de\/news-release\/revealing-hiv-drug-resistance-mechanisms-through-protein-structures\/","og_locale":"de_DE","og_type":"article","og_title":"Revealing HIV drug-resistance mechanisms through protein structures - Salk Institute for Biological Studies","og_description":"LA JOLLA\u2014Salk Institute researchers, in collaboration with the National Institutes of Health, have discovered the molecular mechanisms by which the human immunodeficiency virus (HIV) becomes resistant to Dolutegravir, one of the most effective, clinically used antiviral drugs for treating HIV.","og_url":"https:\/\/www.salk.edu\/de\/news-release\/revealing-hiv-drug-resistance-mechanisms-through-protein-structures\/","og_site_name":"Salk Institute for Biological Studies","article_modified_time":"2023-12-09T04:18:49+00:00","og_image":[{"url":"http:\/\/www.salk.edu\/wp-content\/uploads\/2023\/07\/Lyumkis-PR-20230706-551A3434-458x305.jpg","type":"","width":"","height":""}],"twitter_card":"summary_large_image","twitter_misc":{"Est. reading time":"4 minutes"},"schema":{"@context":"https:\/\/schema.org","@graph":[{"@type":"WebPage","@id":"https:\/\/www.salk.edu\/news-release\/revealing-hiv-drug-resistance-mechanisms-through-protein-structures\/","url":"https:\/\/www.salk.edu\/news-release\/revealing-hiv-drug-resistance-mechanisms-through-protein-structures\/","name":"Revealing HIV drug-resistance mechanisms through protein structures - Salk Institute for Biological Studies","isPartOf":{"@id":"https:\/\/www.salk.edu\/#website"},"primaryImageOfPage":{"@id":"https:\/\/www.salk.edu\/news-release\/revealing-hiv-drug-resistance-mechanisms-through-protein-structures\/#primaryimage"},"image":{"@id":"https:\/\/www.salk.edu\/news-release\/revealing-hiv-drug-resistance-mechanisms-through-protein-structures\/#primaryimage"},"thumbnailUrl":"http:\/\/www.salk.edu\/wp-content\/uploads\/2023\/07\/Lyumkis-PR-20230706-551A3434-458x305.jpg","datePublished":"2023-07-21T07:00:29+00:00","dateModified":"2023-12-09T04:18:49+00:00","breadcrumb":{"@id":"https:\/\/www.salk.edu\/news-release\/revealing-hiv-drug-resistance-mechanisms-through-protein-structures\/#breadcrumb"},"inLanguage":"de-DE","potentialAction":[{"@type":"ReadAction","target":["https:\/\/www.salk.edu\/news-release\/revealing-hiv-drug-resistance-mechanisms-through-protein-structures\/"]}]},{"@type":"ImageObject","inLanguage":"de-DE","@id":"https:\/\/www.salk.edu\/news-release\/revealing-hiv-drug-resistance-mechanisms-through-protein-structures\/#primaryimage","url":"http:\/\/www.salk.edu\/wp-content\/uploads\/2023\/07\/Lyumkis-PR-20230706-551A3434-458x305.jpg","contentUrl":"http:\/\/www.salk.edu\/wp-content\/uploads\/2023\/07\/Lyumkis-PR-20230706-551A3434-458x305.jpg"},{"@type":"BreadcrumbList","@id":"https:\/\/www.salk.edu\/news-release\/revealing-hiv-drug-resistance-mechanisms-through-protein-structures\/#breadcrumb","itemListElement":[{"@type":"ListItem","position":1,"name":"Home","item":"https:\/\/www.salk.edu\/"},{"@type":"ListItem","position":2,"name":"Revealing HIV drug-resistance mechanisms through protein structures"}]},{"@type":"WebSite","@id":"https:\/\/www.salk.edu\/#website","url":"https:\/\/www.salk.edu\/","name":"Salk-Institut f\u00fcr biologische Studien","description":"Die Macht der Wissenschaft","publisher":{"@id":"https:\/\/www.salk.edu\/#organization"},"potentialAction":[{"@type":"SearchAction","target":{"@type":"EntryPoint","urlTemplate":"https:\/\/www.salk.edu\/?s={search_term_string}"},"query-input":{"@type":"PropertyValueSpecification","valueRequired":true,"valueName":"search_term_string"}}],"inLanguage":"de-DE"},{"@type":"Organization","@id":"https:\/\/www.salk.edu\/#organization","name":"Salk-Institut f\u00fcr biologische Studien","url":"https:\/\/www.salk.edu\/","logo":{"@type":"ImageObject","inLanguage":"de-DE","@id":"https:\/\/www.salk.edu\/#\/schema\/logo\/image\/","url":"http:\/\/www.salk.edu\/wp-content\/uploads\/2023\/03\/salk_logo_696.jpg","contentUrl":"http:\/\/www.salk.edu\/wp-content\/uploads\/2023\/03\/salk_logo_696.jpg","width":696,"height":696,"caption":"Salk Institute for Biological Studies"},"image":{"@id":"https:\/\/www.salk.edu\/#\/schema\/logo\/image\/"}}]}},"ACF":{"paper_url":"https:\/\/www.science.org\/doi\/10.1126\/sciadv.adg5953","journal_title":"Science Advances","paper_author_list":"Min Li, Dario Oliveira Passos, Zelin Shan, Steven J. Smith, Qinfang Sun, Avik Biswas, Indrani Choudhuri, Timothy S. Strutzenberg, Allan Haldane, Nanjie Deng, Zhaoyang Li, Xue Zhi Zhao, Lorenzo Briganti, Mamuka Kvaratskhelia, Terrence R. Burke, Jr., Ronald M. Levy, Stephen H. Hughes, Robert Craigie, Dmitry Lyumkis","doi":"10.1126\/sciadv.adg5953","paper_title":"Mechanisms of HIV-1 Integrase Resistance to Dolutegravir and Potent Inhibition of Drug Resistant Variants","subhead":"New Salk Institute research could lead to the development of new HIV therapeutics that overcome resistance to existing drugs","home_photo":"","listing_photo":"","legacy_boilerplate":[],"hide_boilerplate":[],"disable_date":false,"listing_excerpt":"","descriptive_blurb":"","has_journal_cover":false,"og_image_override":false,"gallery":false},"_links":{"self":[{"href":"https:\/\/www.salk.edu\/de\/wp-json\/wp\/v2\/disclosure\/41530","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.salk.edu\/de\/wp-json\/wp\/v2\/disclosure"}],"about":[{"href":"https:\/\/www.salk.edu\/de\/wp-json\/wp\/v2\/types\/disclosure"}],"version-history":[{"count":10,"href":"https:\/\/www.salk.edu\/de\/wp-json\/wp\/v2\/disclosure\/41530\/revisions"}],"predecessor-version":[{"id":41786,"href":"https:\/\/www.salk.edu\/de\/wp-json\/wp\/v2\/disclosure\/41530\/revisions\/41786"}],"wp:attachment":[{"href":"https:\/\/www.salk.edu\/de\/wp-json\/wp\/v2\/media?parent=41530"}],"wp:term":[{"taxonomy":"faculty","embeddable":true,"href":"https:\/\/www.salk.edu\/de\/wp-json\/wp\/v2\/faculty?post=41530"},{"taxonomy":"disease-research","embeddable":true,"href":"https:\/\/www.salk.edu\/de\/wp-json\/wp\/v2\/disease-research?post=41530"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}