K70Q adds high-level tenofovir resistance to "Q151M complex" HIV reverse transcriptase through the enhanced discrimination mechanism
HIV-1 carrying the "Q151M complex" reverse transcriptase (RT) mutations (A62V/V75I/F77L/F116Y/Q151M, or Q151Mc) is resistant to many FDA-approved nucleoside RT inhibitors (NRTIs), but has been considered susceptible to tenofovir disoproxil fumarate (TFV-DF or TDF). We have isolated from a...
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| creator | Hachiya, Atsuko Kodama, Eiichi N Schuckmann, Matthew M Kirby, Karen A Michailidis, Eleftherios Sakagami, Yasuko Oka, Shinichi Singh, Kamalendra Sarafianos, Stefan G |
| description | HIV-1 carrying the "Q151M complex" reverse transcriptase (RT) mutations (A62V/V75I/F77L/F116Y/Q151M, or Q151Mc) is resistant to many FDA-approved nucleoside RT inhibitors (NRTIs), but has been considered susceptible to tenofovir disoproxil fumarate (TFV-DF or TDF). We have isolated from a TFV-DF-treated HIV patient a Q151Mc-containing clinical isolate with high phenotypic resistance to TFV-DF. Analysis of the genotypic and phenotypic testing over the course of this patient's therapy lead us to hypothesize that TFV-DF resistance emerged upon appearance of the previously unreported K70Q mutation in the Q151Mc background. Virological analysis showed that HIV with only K70Q was not significantly resistant to TFV-DF. However, addition of K70Q to the Q151Mc background significantly enhanced resistance to several approved NRTIs, and also resulted in high-level (10-fold) resistance to TFV-DF. Biochemical experiments established that the increased resistance to tenofovir is not the result of enhanced excision, as K70Q/Q151Mc RT exhibited diminished, rather than enhanced ATP-based primer unblocking activity. Pre-steady state kinetic analysis of the recombinant enzymes demonstrated that addition of the K70Q mutation selectively decreases the binding of tenofovir-diphosphate (TFV-DP), resulting in reduced incorporation of TFV into the nascent DNA chain. Molecular dynamics simulations suggest that changes in the hydrogen bonding pattern in the polymerase active site of K70Q/Q151Mc RT may contribute to the observed changes in binding and incorporation of TFV-DP. The novel pattern of TFV-resistance may help adjust therapeutic strategies for NRTI-experienced patients with multi-drug resistant (MDR) mutations. |
| doi_str_mv | 10.1371/journal.pone.0016242 |
| format | Article |
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We have isolated from a TFV-DF-treated HIV patient a Q151Mc-containing clinical isolate with high phenotypic resistance to TFV-DF. Analysis of the genotypic and phenotypic testing over the course of this patient's therapy lead us to hypothesize that TFV-DF resistance emerged upon appearance of the previously unreported K70Q mutation in the Q151Mc background. Virological analysis showed that HIV with only K70Q was not significantly resistant to TFV-DF. However, addition of K70Q to the Q151Mc background significantly enhanced resistance to several approved NRTIs, and also resulted in high-level (10-fold) resistance to TFV-DF. Biochemical experiments established that the increased resistance to tenofovir is not the result of enhanced excision, as K70Q/Q151Mc RT exhibited diminished, rather than enhanced ATP-based primer unblocking activity. Pre-steady state kinetic analysis of the recombinant enzymes demonstrated that addition of the K70Q mutation selectively decreases the binding of tenofovir-diphosphate (TFV-DP), resulting in reduced incorporation of TFV into the nascent DNA chain. Molecular dynamics simulations suggest that changes in the hydrogen bonding pattern in the polymerase active site of K70Q/Q151Mc RT may contribute to the observed changes in binding and incorporation of TFV-DP. The novel pattern of TFV-resistance may help adjust therapeutic strategies for NRTI-experienced patients with multi-drug resistant (MDR) mutations.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0016242</identifier><identifier>PMID: 21249155</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Acquired immune deficiency syndrome ; Adenine - analogs & derivatives ; Adenine - pharmacology ; AIDS ; Antiretroviral drugs ; Binding ; Biology ; Care and treatment ; Catalytic Domain ; Chain dynamics ; Chemical bonds ; Chemistry ; Computer Simulation ; Deoxyribonucleic acid ; Discrimination ; DNA ; DNA polymerases ; Drug approval ; Drug resistance ; Drug Resistance, Viral - genetics ; Enzymes ; HIV ; HIV - genetics ; HIV - isolation & purification ; HIV Reverse Transcriptase - genetics ; Human immunodeficiency virus ; Humans ; Hydrogen ; Hydrogen Bonding ; Kinetics ; Levels ; Medicine ; Molecular dynamics ; Multidrug resistance ; Mutation ; Mutation, Missense ; Organophosphonates - pharmacology ; Protease inhibitors ; Reverse Transcriptase Inhibitors - pharmacology ; RNA-directed DNA polymerase ; Tenofovir</subject><ispartof>PloS one, 2011-01, Vol.6 (1), p.e16242-e16242</ispartof><rights>COPYRIGHT 2011 Public Library of Science</rights><rights>2011 Hachiya et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Hachiya et al. 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c757t-2cc40f225ae4fbe362c05b78ff13b0b3402bd2162cf7a305aafb63d0aca3a9383</citedby><cites>FETCH-LOGICAL-c757t-2cc40f225ae4fbe362c05b78ff13b0b3402bd2162cf7a305aafb63d0aca3a9383</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3020970/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3020970/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79343,79344</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21249155$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Ambrose, Zandrea</contributor><creatorcontrib>Hachiya, Atsuko</creatorcontrib><creatorcontrib>Kodama, Eiichi N</creatorcontrib><creatorcontrib>Schuckmann, Matthew M</creatorcontrib><creatorcontrib>Kirby, Karen A</creatorcontrib><creatorcontrib>Michailidis, Eleftherios</creatorcontrib><creatorcontrib>Sakagami, Yasuko</creatorcontrib><creatorcontrib>Oka, Shinichi</creatorcontrib><creatorcontrib>Singh, Kamalendra</creatorcontrib><creatorcontrib>Sarafianos, Stefan G</creatorcontrib><title>K70Q adds high-level tenofovir resistance to "Q151M complex" HIV reverse transcriptase through the enhanced discrimination mechanism</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>HIV-1 carrying the "Q151M complex" reverse transcriptase (RT) mutations (A62V/V75I/F77L/F116Y/Q151M, or Q151Mc) is resistant to many FDA-approved nucleoside RT inhibitors (NRTIs), but has been considered susceptible to tenofovir disoproxil fumarate (TFV-DF or TDF). We have isolated from a TFV-DF-treated HIV patient a Q151Mc-containing clinical isolate with high phenotypic resistance to TFV-DF. Analysis of the genotypic and phenotypic testing over the course of this patient's therapy lead us to hypothesize that TFV-DF resistance emerged upon appearance of the previously unreported K70Q mutation in the Q151Mc background. Virological analysis showed that HIV with only K70Q was not significantly resistant to TFV-DF. However, addition of K70Q to the Q151Mc background significantly enhanced resistance to several approved NRTIs, and also resulted in high-level (10-fold) resistance to TFV-DF. Biochemical experiments established that the increased resistance to tenofovir is not the result of enhanced excision, as K70Q/Q151Mc RT exhibited diminished, rather than enhanced ATP-based primer unblocking activity. Pre-steady state kinetic analysis of the recombinant enzymes demonstrated that addition of the K70Q mutation selectively decreases the binding of tenofovir-diphosphate (TFV-DP), resulting in reduced incorporation of TFV into the nascent DNA chain. Molecular dynamics simulations suggest that changes in the hydrogen bonding pattern in the polymerase active site of K70Q/Q151Mc RT may contribute to the observed changes in binding and incorporation of TFV-DP. The novel pattern of TFV-resistance may help adjust therapeutic strategies for NRTI-experienced patients with multi-drug resistant (MDR) mutations.</description><subject>Acquired immune deficiency syndrome</subject><subject>Adenine - analogs & derivatives</subject><subject>Adenine - pharmacology</subject><subject>AIDS</subject><subject>Antiretroviral drugs</subject><subject>Binding</subject><subject>Biology</subject><subject>Care and treatment</subject><subject>Catalytic Domain</subject><subject>Chain dynamics</subject><subject>Chemical bonds</subject><subject>Chemistry</subject><subject>Computer Simulation</subject><subject>Deoxyribonucleic acid</subject><subject>Discrimination</subject><subject>DNA</subject><subject>DNA polymerases</subject><subject>Drug approval</subject><subject>Drug resistance</subject><subject>Drug Resistance, Viral - genetics</subject><subject>Enzymes</subject><subject>HIV</subject><subject>HIV - genetics</subject><subject>HIV - isolation & purification</subject><subject>HIV Reverse Transcriptase - genetics</subject><subject>Human immunodeficiency virus</subject><subject>Humans</subject><subject>Hydrogen</subject><subject>Hydrogen Bonding</subject><subject>Kinetics</subject><subject>Levels</subject><subject>Medicine</subject><subject>Molecular dynamics</subject><subject>Multidrug resistance</subject><subject>Mutation</subject><subject>Mutation, Missense</subject><subject>Organophosphonates - pharmacology</subject><subject>Protease inhibitors</subject><subject>Reverse Transcriptase Inhibitors - pharmacology</subject><subject>RNA-directed DNA polymerase</subject><subject>Tenofovir</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNk8tu1DAUhiMEoqXwBgiiIoFYzOBrnGyQqgroiKKqXLq1HF8mrhJ7sJNR2fPgOExaTVAXKAvHPt_5z8kfnyx7DsESYgbfXfshONEuN97pJQCwQAQ9yA5hhdGiQAA_3Hs_yJ7EeA0AxWVRPM4OEESkgpQeZr8_M3CZC6Vi3th1s2j1Vrd5r503fmtDHnS0sRdO6rz3-fElpPBLLn23afXNcX62ukrEVoeYwkG4KIPd9GLcNcEP6yatOteuGQVUruwIdNaJ3nqXd1qmgI3d0-yREW3Uz6b1KPvx8cP307PF-cWn1enJ-UIyyvoFkpIAgxAVmpha4wJJQGtWGgNxDWpMAKoVSkZIwwQGVAhTF1gBIQUWFS7xUfZyp7tpfeSTgZFDVBFWlpSSRKx2hPLimm9SsyL84l5Y_vfAhzUXobey1ZzWqTAxBWMFJbCEtRKkLmWtgDI4tZm03k_VhrrTSmqXLGpnovOIsw1f-y3HAIGKgSTwZhII_uegY8-7ZKBuW-G0HyIvSVFWDJY4ka_-Ie__uIlai9S_dcansnLU5CeEFRVgFMJELe-h0qN0Z2W6bMam81nC21lCYnp906_FECNfffv6_-zF1Zx9vcc2WrR9E307jHcnzkGyA2XwMQZt7jyGgI-zcusGH2eFT7OS0l7s_5-7pNvhwH8AGiYQKA</recordid><startdate>20110113</startdate><enddate>20110113</enddate><creator>Hachiya, Atsuko</creator><creator>Kodama, Eiichi N</creator><creator>Schuckmann, Matthew M</creator><creator>Kirby, Karen A</creator><creator>Michailidis, Eleftherios</creator><creator>Sakagami, Yasuko</creator><creator>Oka, Shinichi</creator><creator>Singh, Kamalendra</creator><creator>Sarafianos, Stefan G</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20110113</creationdate><title>K70Q adds high-level tenofovir resistance to "Q151M complex" HIV reverse transcriptase through the enhanced discrimination mechanism</title><author>Hachiya, Atsuko ; Kodama, Eiichi N ; Schuckmann, Matthew M ; Kirby, Karen A ; Michailidis, Eleftherios ; Sakagami, Yasuko ; Oka, Shinichi ; Singh, Kamalendra ; Sarafianos, Stefan G</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c757t-2cc40f225ae4fbe362c05b78ff13b0b3402bd2162cf7a305aafb63d0aca3a9383</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Acquired immune deficiency syndrome</topic><topic>Adenine - 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We have isolated from a TFV-DF-treated HIV patient a Q151Mc-containing clinical isolate with high phenotypic resistance to TFV-DF. Analysis of the genotypic and phenotypic testing over the course of this patient's therapy lead us to hypothesize that TFV-DF resistance emerged upon appearance of the previously unreported K70Q mutation in the Q151Mc background. Virological analysis showed that HIV with only K70Q was not significantly resistant to TFV-DF. However, addition of K70Q to the Q151Mc background significantly enhanced resistance to several approved NRTIs, and also resulted in high-level (10-fold) resistance to TFV-DF. Biochemical experiments established that the increased resistance to tenofovir is not the result of enhanced excision, as K70Q/Q151Mc RT exhibited diminished, rather than enhanced ATP-based primer unblocking activity. Pre-steady state kinetic analysis of the recombinant enzymes demonstrated that addition of the K70Q mutation selectively decreases the binding of tenofovir-diphosphate (TFV-DP), resulting in reduced incorporation of TFV into the nascent DNA chain. Molecular dynamics simulations suggest that changes in the hydrogen bonding pattern in the polymerase active site of K70Q/Q151Mc RT may contribute to the observed changes in binding and incorporation of TFV-DP. The novel pattern of TFV-resistance may help adjust therapeutic strategies for NRTI-experienced patients with multi-drug resistant (MDR) mutations.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>21249155</pmid><doi>10.1371/journal.pone.0016242</doi><tpages>e16242</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2011-01, Vol.6 (1), p.e16242-e16242 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1294788554 |
| source | Public Library of Science (PLoS) Journals Open Access; MEDLINE; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Acquired immune deficiency syndrome Adenine - analogs & derivatives Adenine - pharmacology AIDS Antiretroviral drugs Binding Biology Care and treatment Catalytic Domain Chain dynamics Chemical bonds Chemistry Computer Simulation Deoxyribonucleic acid Discrimination DNA DNA polymerases Drug approval Drug resistance Drug Resistance, Viral - genetics Enzymes HIV HIV - genetics HIV - isolation & purification HIV Reverse Transcriptase - genetics Human immunodeficiency virus Humans Hydrogen Hydrogen Bonding Kinetics Levels Medicine Molecular dynamics Multidrug resistance Mutation Mutation, Missense Organophosphonates - pharmacology Protease inhibitors Reverse Transcriptase Inhibitors - pharmacology RNA-directed DNA polymerase Tenofovir |
| title | K70Q adds high-level tenofovir resistance to "Q151M complex" HIV reverse transcriptase through the enhanced discrimination mechanism |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-28T19%3A01%3A44IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=K70Q%20adds%20high-level%20tenofovir%20resistance%20to%20%22Q151M%20complex%22%20HIV%20reverse%20transcriptase%20through%20the%20enhanced%20discrimination%20mechanism&rft.jtitle=PloS%20one&rft.au=Hachiya,%20Atsuko&rft.date=2011-01-13&rft.volume=6&rft.issue=1&rft.spage=e16242&rft.epage=e16242&rft.pages=e16242-e16242&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0016242&rft_dat=%3Cgale_plos_%3EA476907511%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1294788554&rft_id=info:pmid/21249155&rft_galeid=A476907511&rft_doaj_id=oai_doaj_org_article_5b8ff4f677654181bda4b8cbd0df30f2&rfr_iscdi=true |