Primary mutations selected in vitro with raltegravir confer large fold changes in susceptibility to first-generation integrase inhibitors, but minor fold changes to inhibitors with second-generation resistance profiles
Abstract Emergence of resistance to raltegravir reduces its treatment efficacy in HIV-1-infected patients. To delineate the effect of resistance mutations on viral susceptibility to integrase inhibitors, in vitro resistance selections with raltegravir and with MK-2048, an integrase inhibitor with a...
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| Veröffentlicht in: | Virology (New York, N.Y.) N.Y.), 2010-07, Vol.402 (2), p.338-346 |
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| container_title | Virology (New York, N.Y.) |
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| creator | Goethals, Olivia Vos, Ann Van Ginderen, Marcia Geluykens, Peggy Smits, Veerle Schols, Dominique Hertogs, Kurt Clayton, Reginald |
| description | Abstract Emergence of resistance to raltegravir reduces its treatment efficacy in HIV-1-infected patients. To delineate the effect of resistance mutations on viral susceptibility to integrase inhibitors, in vitro resistance selections with raltegravir and with MK-2048, an integrase inhibitor with a second-generation-like resistance profile, were performed. Mutation Q148R arose in four out of six raltegravir-selected resistant viruses. In addition, mutations Q148K and N155H were selected. In the same time frame, no mutations were selected with MK-2048. Q148H/K/R and N155H conferred resistance to raltegravir, but only minor changes in susceptibility to MK-2048. V54I, a previously unreported mutation, selected with raltegravir, was identified as a possible compensation mutation. Mechanisms by which N155H, Q148H/K/R, Y143R and E92Q confer resistance are proposed based on a structural model of integrase. These data improve the understanding of resistance against raltegravir and cross-resistance to MK-2048 and other integrase inhibitors, which will aid in the discovery of second-generation integrase inhibitors. |
| doi_str_mv | 10.1016/j.virol.2010.03.034 |
| format | Article |
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To delineate the effect of resistance mutations on viral susceptibility to integrase inhibitors, in vitro resistance selections with raltegravir and with MK-2048, an integrase inhibitor with a second-generation-like resistance profile, were performed. Mutation Q148R arose in four out of six raltegravir-selected resistant viruses. In addition, mutations Q148K and N155H were selected. In the same time frame, no mutations were selected with MK-2048. Q148H/K/R and N155H conferred resistance to raltegravir, but only minor changes in susceptibility to MK-2048. V54I, a previously unreported mutation, selected with raltegravir, was identified as a possible compensation mutation. Mechanisms by which N155H, Q148H/K/R, Y143R and E92Q confer resistance are proposed based on a structural model of integrase. These data improve the understanding of resistance against raltegravir and cross-resistance to MK-2048 and other integrase inhibitors, which will aid in the discovery of second-generation integrase inhibitors.</description><identifier>ISSN: 0042-6822</identifier><identifier>EISSN: 1096-0341</identifier><identifier>DOI: 10.1016/j.virol.2010.03.034</identifier><identifier>PMID: 20421122</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Amino Acid Substitution - genetics ; Anti-HIV Agents - pharmacology ; DNA Mutational Analysis ; Drug Resistance, Viral ; HIV ; HIV Integrase - chemistry ; HIV Integrase - genetics ; HIV Integrase Inhibitors - pharmacology ; HIV-1 - drug effects ; HIV-1 - genetics ; Human immunodeficiency virus ; Humans ; Infectious Disease ; integrase ; MK-2048 ; Models, Molecular ; Mutation, Missense ; Protein Structure, Tertiary ; Pyrrolidinones - pharmacology ; raltegravir ; Raltegravir Potassium ; resistance</subject><ispartof>Virology (New York, N.Y.), 2010-07, Vol.402 (2), p.338-346</ispartof><rights>Elsevier Inc.</rights><rights>2010 Elsevier Inc.</rights><rights>Copyright 2010 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c445t-c16e66a31d62b4e2d099043a926a721ad6b5af855e2fce3d73f7ca7067d0688d3</citedby><cites>FETCH-LOGICAL-c445t-c16e66a31d62b4e2d099043a926a721ad6b5af855e2fce3d73f7ca7067d0688d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.virol.2010.03.034$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20421122$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Goethals, Olivia</creatorcontrib><creatorcontrib>Vos, Ann</creatorcontrib><creatorcontrib>Van Ginderen, Marcia</creatorcontrib><creatorcontrib>Geluykens, Peggy</creatorcontrib><creatorcontrib>Smits, Veerle</creatorcontrib><creatorcontrib>Schols, Dominique</creatorcontrib><creatorcontrib>Hertogs, Kurt</creatorcontrib><creatorcontrib>Clayton, Reginald</creatorcontrib><title>Primary mutations selected in vitro with raltegravir confer large fold changes in susceptibility to first-generation integrase inhibitors, but minor fold changes to inhibitors with second-generation resistance profiles</title><title>Virology (New York, N.Y.)</title><addtitle>Virology</addtitle><description>Abstract Emergence of resistance to raltegravir reduces its treatment efficacy in HIV-1-infected patients. To delineate the effect of resistance mutations on viral susceptibility to integrase inhibitors, in vitro resistance selections with raltegravir and with MK-2048, an integrase inhibitor with a second-generation-like resistance profile, were performed. Mutation Q148R arose in four out of six raltegravir-selected resistant viruses. In addition, mutations Q148K and N155H were selected. In the same time frame, no mutations were selected with MK-2048. Q148H/K/R and N155H conferred resistance to raltegravir, but only minor changes in susceptibility to MK-2048. V54I, a previously unreported mutation, selected with raltegravir, was identified as a possible compensation mutation. Mechanisms by which N155H, Q148H/K/R, Y143R and E92Q confer resistance are proposed based on a structural model of integrase. These data improve the understanding of resistance against raltegravir and cross-resistance to MK-2048 and other integrase inhibitors, which will aid in the discovery of second-generation integrase inhibitors.</description><subject>Amino Acid Substitution - genetics</subject><subject>Anti-HIV Agents - pharmacology</subject><subject>DNA Mutational Analysis</subject><subject>Drug Resistance, Viral</subject><subject>HIV</subject><subject>HIV Integrase - chemistry</subject><subject>HIV Integrase - genetics</subject><subject>HIV Integrase Inhibitors - pharmacology</subject><subject>HIV-1 - drug effects</subject><subject>HIV-1 - genetics</subject><subject>Human immunodeficiency virus</subject><subject>Humans</subject><subject>Infectious Disease</subject><subject>integrase</subject><subject>MK-2048</subject><subject>Models, Molecular</subject><subject>Mutation, Missense</subject><subject>Protein Structure, Tertiary</subject><subject>Pyrrolidinones - pharmacology</subject><subject>raltegravir</subject><subject>Raltegravir Potassium</subject><subject>resistance</subject><issn>0042-6822</issn><issn>1096-0341</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFUl2rEzEQXUTxXqu_QJC8-eLWfOxmuw8KcvELLiiozyFNZtvUdFMz2Ur_qr_GaXv9fLkwkElyzplhzlTVY8Hnggv9fDPfh5ziXHJ64YqiuVNdCt7rmlJxt7rkvJG1Xkh5UT1A3HC6dx2_X11I-hBCysvqx8cctjYf2HYqtoQ0IkOI4Ap4Fka2DyUn9j2UNcs2FlhlS0WZS-MAmUWbV8CGFD1zazuuAI8cnNDBroRliKEcWElsCBlLvYIR8qkGoU5SCJStCVhSxmdsORW2DWPK_0qSwB_UuRcE6sD_rZgBAxY7OmC7nIYQAR9W9wYbER7dnLPqy5vXn6_e1dcf3r6_enVdu6ZpS-2EBq2tEl7LZQPS877njbK91LaTwnq9bO2waFuQgwPlOzV0znZcd57rxcKrWfX0rEuFv02AxWwDTSBGO0Ka0HRN2yvdc3U7UimhOSf4rFJnpMsJMcNgdmefjODm6L7ZmJP75ui-4YqiIdaTG_1puQX_m_PLbgK8OAOA5rEPkA26ADQ0HzJ5bnwKtxR4-R_fxTAGZ-NXOABu0pRHGrURBqXh5tNxAY_7J2j1pOha9RPMx93E</recordid><startdate>20100705</startdate><enddate>20100705</enddate><creator>Goethals, Olivia</creator><creator>Vos, Ann</creator><creator>Van Ginderen, Marcia</creator><creator>Geluykens, Peggy</creator><creator>Smits, Veerle</creator><creator>Schols, Dominique</creator><creator>Hertogs, Kurt</creator><creator>Clayton, Reginald</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</scope><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>7X8</scope><scope>7U9</scope><scope>H94</scope></search><sort><creationdate>20100705</creationdate><title>Primary mutations selected in vitro with raltegravir confer large fold changes in susceptibility to first-generation integrase inhibitors, but minor fold changes to inhibitors with second-generation resistance profiles</title><author>Goethals, Olivia ; 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To delineate the effect of resistance mutations on viral susceptibility to integrase inhibitors, in vitro resistance selections with raltegravir and with MK-2048, an integrase inhibitor with a second-generation-like resistance profile, were performed. Mutation Q148R arose in four out of six raltegravir-selected resistant viruses. In addition, mutations Q148K and N155H were selected. In the same time frame, no mutations were selected with MK-2048. Q148H/K/R and N155H conferred resistance to raltegravir, but only minor changes in susceptibility to MK-2048. V54I, a previously unreported mutation, selected with raltegravir, was identified as a possible compensation mutation. Mechanisms by which N155H, Q148H/K/R, Y143R and E92Q confer resistance are proposed based on a structural model of integrase. 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| ispartof | Virology (New York, N.Y.), 2010-07, Vol.402 (2), p.338-346 |
| issn | 0042-6822 1096-0341 |
| language | eng |
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| source | MEDLINE; Access via ScienceDirect (Elsevier); EZB-FREE-00999 freely available EZB journals |
| subjects | Amino Acid Substitution - genetics Anti-HIV Agents - pharmacology DNA Mutational Analysis Drug Resistance, Viral HIV HIV Integrase - chemistry HIV Integrase - genetics HIV Integrase Inhibitors - pharmacology HIV-1 - drug effects HIV-1 - genetics Human immunodeficiency virus Humans Infectious Disease integrase MK-2048 Models, Molecular Mutation, Missense Protein Structure, Tertiary Pyrrolidinones - pharmacology raltegravir Raltegravir Potassium resistance |
| title | Primary mutations selected in vitro with raltegravir confer large fold changes in susceptibility to first-generation integrase inhibitors, but minor fold changes to inhibitors with second-generation resistance profiles |
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