HIV-1 reverse transcriptase connection subdomain mutations involved in resistance to approved non-nucleoside inhibitors

The human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) is a major target of antiretroviral intervention. Non-nucleoside RT inhibitors (NNRTIs) bind to a hydrophobic pocket located away from the DNA polymerase catalytic site of the RT. Approved NNRTIs are nevirapine, delavirdine,...

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Autores: Menéndez-Arias, Luis, Betancor, Gilberto, Matamoros Grande, Tania
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2011
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/340988
Acceso en línea:http://hdl.handle.net/10261/340988
Access Level:acceso abierto
Palabra clave:HIV
Reverse transcriptase
Drug resistance
Non-nucleoside RT inhibitors
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spelling HIV-1 reverse transcriptase connection subdomain mutations involved in resistance to approved non-nucleoside inhibitorsMenéndez-Arias, LuisBetancor, GilbertoMatamoros Grande, TaniaHIVReverse transcriptaseDrug resistanceNon-nucleoside RT inhibitorsThe human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) is a major target of antiretroviral intervention. Non-nucleoside RT inhibitors (NNRTIs) bind to a hydrophobic pocket located away from the DNA polymerase catalytic site of the RT. Approved NNRTIs are nevirapine, delavirdine, efavirenz, etravirine and rilpivirine. This review describes how these inhibitors affect RT function, the structural basis of NNRTI binding, and the role of specific amino acid substitutions at the NNRTI binding pocket in the acquisition of high-level drug resistance. However, two or more amino acid substitutions are required to achieve >20-fold decreased susceptibility to recently developed NNRTIs such as etravirine or rilpivirine, in phenotypic assays. While genotypic analysis of HIV-1 isolates in infected patients is usually restricted to residues 1-250 of the RT, recent reports indicate that several residues in the connection subdomain of the RT (comprising residues 319-426) could also modulate NNRTI resistance. Examples are Y318F or W, N348I, A376S and T369I or V. Tyr-318 participates in NNRTI binding, but other amino acid substitutions in the connection subdomain may affect resistance through an indirect mechanism. Studies on the effects of N348I and A376S on NNRTI resistance indicate that these changes could affect inhibitor binding by altering the interaction between RT subunits or between the RT and the template-primer. Moreover, those mutations could also modulate RNase H activity not only during DNA strand elongation, but also at the initiation of plus strand DNA synthesis as demonstrated for the N348I mutation. © 2011 Elsevier B.V.Work in the authors’ laboratory is supported grants of the Ministry of Science and Innovation of Spain (BIO2010/15542), Fundación para la Investigación y Prevención del SIDA en España (FIPSE) (grant 36771/08), Fondo de Investigación Sanitaria (through the “Red Temática de Investigación Cooperativa en SIDA” RD06/0006), and an institutional grant from the Fundación Ramón Areces.Elsevier BVFundación Ramón ArecesMinisterio de Ciencia e Innovación (España)Fundación para la Investigación y la Prevención del Sida en EspañaRed Española de Investigación en SIDAConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2023202320112023info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_dcae04bcPostprintinfo:eu-repo/semantics/acceptedVersionapplication/pdfhttp://hdl.handle.net/10261/340988reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Ingléshttp://dx.doi.org/10.1016/j.antiviral.2011.08.020Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3409882026-05-22T06:33:51Z
dc.title.none.fl_str_mv HIV-1 reverse transcriptase connection subdomain mutations involved in resistance to approved non-nucleoside inhibitors
title HIV-1 reverse transcriptase connection subdomain mutations involved in resistance to approved non-nucleoside inhibitors
spellingShingle HIV-1 reverse transcriptase connection subdomain mutations involved in resistance to approved non-nucleoside inhibitors
Menéndez-Arias, Luis
HIV
Reverse transcriptase
Drug resistance
Non-nucleoside RT inhibitors
title_short HIV-1 reverse transcriptase connection subdomain mutations involved in resistance to approved non-nucleoside inhibitors
title_full HIV-1 reverse transcriptase connection subdomain mutations involved in resistance to approved non-nucleoside inhibitors
title_fullStr HIV-1 reverse transcriptase connection subdomain mutations involved in resistance to approved non-nucleoside inhibitors
title_full_unstemmed HIV-1 reverse transcriptase connection subdomain mutations involved in resistance to approved non-nucleoside inhibitors
title_sort HIV-1 reverse transcriptase connection subdomain mutations involved in resistance to approved non-nucleoside inhibitors
dc.creator.none.fl_str_mv Menéndez-Arias, Luis
Betancor, Gilberto
Matamoros Grande, Tania
author Menéndez-Arias, Luis
author_facet Menéndez-Arias, Luis
Betancor, Gilberto
Matamoros Grande, Tania
author_role author
author2 Betancor, Gilberto
Matamoros Grande, Tania
author2_role author
author
dc.contributor.none.fl_str_mv Fundación Ramón Areces
Ministerio de Ciencia e Innovación (España)
Fundación para la Investigación y la Prevención del Sida en España
Red Española de Investigación en SIDA
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv HIV
Reverse transcriptase
Drug resistance
Non-nucleoside RT inhibitors
topic HIV
Reverse transcriptase
Drug resistance
Non-nucleoside RT inhibitors
description The human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) is a major target of antiretroviral intervention. Non-nucleoside RT inhibitors (NNRTIs) bind to a hydrophobic pocket located away from the DNA polymerase catalytic site of the RT. Approved NNRTIs are nevirapine, delavirdine, efavirenz, etravirine and rilpivirine. This review describes how these inhibitors affect RT function, the structural basis of NNRTI binding, and the role of specific amino acid substitutions at the NNRTI binding pocket in the acquisition of high-level drug resistance. However, two or more amino acid substitutions are required to achieve >20-fold decreased susceptibility to recently developed NNRTIs such as etravirine or rilpivirine, in phenotypic assays. While genotypic analysis of HIV-1 isolates in infected patients is usually restricted to residues 1-250 of the RT, recent reports indicate that several residues in the connection subdomain of the RT (comprising residues 319-426) could also modulate NNRTI resistance. Examples are Y318F or W, N348I, A376S and T369I or V. Tyr-318 participates in NNRTI binding, but other amino acid substitutions in the connection subdomain may affect resistance through an indirect mechanism. Studies on the effects of N348I and A376S on NNRTI resistance indicate that these changes could affect inhibitor binding by altering the interaction between RT subunits or between the RT and the template-primer. Moreover, those mutations could also modulate RNase H activity not only during DNA strand elongation, but also at the initiation of plus strand DNA synthesis as demonstrated for the N348I mutation. © 2011 Elsevier B.V.
publishDate 2011
dc.date.none.fl_str_mv 2011
2023
2023
2023
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_dcae04bc
Postprint
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/340988
url http://hdl.handle.net/10261/340988
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv http://dx.doi.org/10.1016/j.antiviral.2011.08.020
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Elsevier BV
publisher.none.fl_str_mv Elsevier BV
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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