HIV-1 Protease Dimer Interface Mutations that Compensate for Viral Reverse Transcriptase Instability in Infectious Virions

Article available at http://dx.doi.org/10.1016/j.jmb.2007.06.073

Detalhes bibliográficos
Autores: Olivares, Isabel, Mulky, Alok, Boross, Peter I., Tözsér, József, López-Galíndez, Cecilio, Kappes, John C., Menéndez-Arias, Luis
Formato: artículo
Fecha de publicación:2007
País:España
Recursos:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/4924
Acesso em linha:http://hdl.handle.net/10261/4924
Access Level:acceso abierto
Palavra-chave:HIV
Reverse transcriptase
Protease
Retrovirus
Fitness
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spelling HIV-1 Protease Dimer Interface Mutations that Compensate for Viral Reverse Transcriptase Instability in Infectious VirionsOlivares, IsabelMulky, AlokBoross, Peter I.Tözsér, JózsefLópez-Galíndez, CecilioKappes, John C.Menéndez-Arias, LuisHIVReverse transcriptaseProteaseRetrovirusFitnessArticle available at http://dx.doi.org/10.1016/j.jmb.2007.06.073Mature enzymes encoded within the human immunodeficiency virus type 1 (HIV-1) genome (protease (PR), reverse transcriptase (RT) and integrase (IN)) derive from proteolytic processing of a large polyprotein (Gag-Pol). Gag-Pol processing is catalyzed by the viral PR, which is active as a homodimer. The HIV-1 RT functions as a heterodimer (p66/p51) composed of subunits of 560 and 440 amino acid residues, respectively. Both subunits have identical amino acid sequence, but p51 lacks 120 residues that are removed by the HIV-1 PR during viral maturation. While p66 is the catalytic subunit, p51 has a primarily structural role. Amino acid substitutions affecting the stability of p66/p51 (i.e. F130W) have a deleterious effect on viral fitness. Previously, we showed that the effects of F130W are mediated by p51 and can be compensated by mutation T58S. While studying the dynamics of emergence of the compensatory mutation, we observed that mutations in the viral PR-coding region were selected in HIV clones containing the RT substitution F130W, before the imposition of T58S/F130W mutations. The PR mutations identified (G94S and T96S) improved the replication capacity of the F130W mutant virus. By using a trans-complementation assay, we demonstrate that the loss of p66/p51 heterodimer stability caused by Trp130 can be attributed to an increased susceptibility of RT to viral PR degradation. Recombinant HIV-1 PRs bearing mutations G94S or T96S showed decreased dimer stability and reduced catalytic efficiency. These results were consistent with crystallographic data showing the location of both residues in the PR dimerization interfaceThis work was supported, in part, by Fondo de Investigación Sanitaria (through the “Red Temática de Investigación Cooperativa en SIDA” RD06/006). In addition, work in the CBMSO (Madrid) was supported by grant BIO2003/01175 (Spanish Ministry of Education and Science) and an institutional grant from the Fundación Ramón Areces. Work in the CNM (Majadahonda) was supported by grants SAF2002/626, SAF2003/4987 and SAF2005/3833 (Spanish Ministry of Education and Science), and by the Plan Nacional sobre el SIDA. Work in the UAB was supported by National Institutes of Health grants CA73470 and AI47714 and core facilities of the Birmingham Center for AIDS Research (P30-AI-27767). Support from the Spanish-Hungarian Intergovernmental Science and Technology Cooperation Program (grant HH2005-0020) is acknowledgedPeer reviewedElsevierInstituto de Salud Carlos IIIMinisterio de Educación y Ciencia (España)Fundación Ramón ArecesMinisterio de Sanidad, Servicios Sociales e Igualdad (España)National Institutes of Health (US)Red Española de Investigación en SIDA200820082007info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501992622 bytesapplication/pdfhttp://hdl.handle.net/10261/4924reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglésinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/49242026-05-22T06:33:51Z
dc.title.none.fl_str_mv HIV-1 Protease Dimer Interface Mutations that Compensate for Viral Reverse Transcriptase Instability in Infectious Virions
title HIV-1 Protease Dimer Interface Mutations that Compensate for Viral Reverse Transcriptase Instability in Infectious Virions
spellingShingle HIV-1 Protease Dimer Interface Mutations that Compensate for Viral Reverse Transcriptase Instability in Infectious Virions
Olivares, Isabel
HIV
Reverse transcriptase
Protease
Retrovirus
Fitness
title_short HIV-1 Protease Dimer Interface Mutations that Compensate for Viral Reverse Transcriptase Instability in Infectious Virions
title_full HIV-1 Protease Dimer Interface Mutations that Compensate for Viral Reverse Transcriptase Instability in Infectious Virions
title_fullStr HIV-1 Protease Dimer Interface Mutations that Compensate for Viral Reverse Transcriptase Instability in Infectious Virions
title_full_unstemmed HIV-1 Protease Dimer Interface Mutations that Compensate for Viral Reverse Transcriptase Instability in Infectious Virions
title_sort HIV-1 Protease Dimer Interface Mutations that Compensate for Viral Reverse Transcriptase Instability in Infectious Virions
dc.creator.none.fl_str_mv Olivares, Isabel
Mulky, Alok
Boross, Peter I.
Tözsér, József
López-Galíndez, Cecilio
Kappes, John C.
Menéndez-Arias, Luis
author Olivares, Isabel
author_facet Olivares, Isabel
Mulky, Alok
Boross, Peter I.
Tözsér, József
López-Galíndez, Cecilio
Kappes, John C.
Menéndez-Arias, Luis
author_role author
author2 Mulky, Alok
Boross, Peter I.
Tözsér, József
López-Galíndez, Cecilio
Kappes, John C.
Menéndez-Arias, Luis
author2_role author
author
author
author
author
author
dc.contributor.none.fl_str_mv Instituto de Salud Carlos III
Ministerio de Educación y Ciencia (España)
Fundación Ramón Areces
Ministerio de Sanidad, Servicios Sociales e Igualdad (España)
National Institutes of Health (US)
Red Española de Investigación en SIDA
dc.subject.none.fl_str_mv HIV
Reverse transcriptase
Protease
Retrovirus
Fitness
topic HIV
Reverse transcriptase
Protease
Retrovirus
Fitness
description Article available at http://dx.doi.org/10.1016/j.jmb.2007.06.073
publishDate 2007
dc.date.none.fl_str_mv 2007
2008
2008
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/4924
url http://hdl.handle.net/10261/4924
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 992622 bytes
application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
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
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