Effect of Natural Polymorphisms in the HIV-1 CRF02_AG Protease on Protease Inhibitor Hypersusceptibility

Detalhes bibliográficos
Autor(a) principal: Santos, Andre F. A.
Data de Publicação: 2012
Outros Autores: Tebit, Denis M., Lalonde, Matthew S., Abecasis, Ana B., Ratcliff, Annette, Camacho, Ricardo J., Diaz, Ricardo S. [UNIFESP], Herchenroeder, Ottmar, Soares, Marcelo A., Arts, Eric J.
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Institucional da UNIFESP
Texto Completo: http://dx.doi.org/10.1128/AAC.06079-11
http://repositorio.unifesp.br/handle/11600/34822
Resumo: Hypersusceptibility (HS) to inhibition by different antiretroviral drugs (ARVs) among diverse HIV-infected individuals may be a misnomer because clinical response to treatment is evaluated in relation to subtype B infections while drug susceptibility of the infecting virus, regardless of subtype, is compared to a subtype B HIV-1 laboratory strain (NL4-3 or IIIB). Mounting evidence suggests that HS to different ARVs may result in better treatment outcome just as drug resistance leads to treatment failure. We have identified key amino acid polymorphisms in the protease coding region of a non-B HIV-1 subtype linked to protease inhibitor HS, namely, 17E and 64M in CRF02_AG. These HS-linked polymorphisms were introduced in the BD6-15 CRF02_AG molecular clone and tested for inhibition using a panel of protease inhibitors. in general, suspected HS-linked polymorphisms did increase susceptibility to specific protease inhibitors such as amprenavir and atazanavir, but the combination of the 17E/64M polymorphisms showed greater HS. These two mutations were found at low frequencies but linked in a sequence database of over 700 protease sequences of CRF02_AG. in direct head-to-head virus competitions, CRF02_AG harboring the 17E/64M polymorphisms also had higher replicative fitness than did the 17E or the 64M polymorphism in the CFR02_AG clone. These findings suggest that subtype-specific, linked polymorphisms can result in hypersusceptibility to ARVs. Considering the potential benefit of HS to treatment outcome, screening for potential HS-linked polymorphisms as well as preexisting drug resistance mutations in treatment-naive patients may guide the choice of ARVs for the best treatment outcome.
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spelling Effect of Natural Polymorphisms in the HIV-1 CRF02_AG Protease on Protease Inhibitor HypersusceptibilityHypersusceptibility (HS) to inhibition by different antiretroviral drugs (ARVs) among diverse HIV-infected individuals may be a misnomer because clinical response to treatment is evaluated in relation to subtype B infections while drug susceptibility of the infecting virus, regardless of subtype, is compared to a subtype B HIV-1 laboratory strain (NL4-3 or IIIB). Mounting evidence suggests that HS to different ARVs may result in better treatment outcome just as drug resistance leads to treatment failure. We have identified key amino acid polymorphisms in the protease coding region of a non-B HIV-1 subtype linked to protease inhibitor HS, namely, 17E and 64M in CRF02_AG. These HS-linked polymorphisms were introduced in the BD6-15 CRF02_AG molecular clone and tested for inhibition using a panel of protease inhibitors. in general, suspected HS-linked polymorphisms did increase susceptibility to specific protease inhibitors such as amprenavir and atazanavir, but the combination of the 17E/64M polymorphisms showed greater HS. These two mutations were found at low frequencies but linked in a sequence database of over 700 protease sequences of CRF02_AG. in direct head-to-head virus competitions, CRF02_AG harboring the 17E/64M polymorphisms also had higher replicative fitness than did the 17E or the 64M polymorphism in the CFR02_AG clone. These findings suggest that subtype-specific, linked polymorphisms can result in hypersusceptibility to ARVs. Considering the potential benefit of HS to treatment outcome, screening for potential HS-linked polymorphisms as well as preexisting drug resistance mutations in treatment-naive patients may guide the choice of ARVs for the best treatment outcome.Case Western Reserve Univ, Cleveland, OH 44106 USAUniv Fed Rio de Janeiro, Dept Genet, Lab Virol Humana, Rio de Janeiro, BrazilHosp Egas Moniz, Lisbon, PortugalUniversidade Federal de São Paulo, Lab Retrovirol, São Paulo, BrazilUniv Rostock, Rostock, GermanyInst Nacl Canc, Programa Genet, Rio de Janeiro, BrazilUniversidade Federal de São Paulo, Lab Retrovirol, São Paulo, BrazilWeb of ScienceAmer Soc MicrobiologyCase Western Reserve UnivUniversidade Federal do Rio de Janeiro (UFRJ)Hosp Egas MonizUniversidade Federal de São Paulo (UNIFESP)Univ RostockInst Nacl CancSantos, Andre F. A.Tebit, Denis M.Lalonde, Matthew S.Abecasis, Ana B.Ratcliff, AnnetteCamacho, Ricardo J.Diaz, Ricardo S. [UNIFESP]Herchenroeder, OttmarSoares, Marcelo A.Arts, Eric J.2016-01-24T14:27:09Z2016-01-24T14:27:09Z2012-05-01info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion2719-2725application/pdfhttp://dx.doi.org/10.1128/AAC.06079-11Antimicrobial Agents and Chemotherapy. Washington: Amer Soc Microbiology, v. 56, n. 5, p. 2719-2725, 2012.10.1128/AAC.06079-11WOS000302790400069.pdf0066-4804http://repositorio.unifesp.br/handle/11600/34822WOS:000302790400069engAntimicrobial Agents and Chemotherapyinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da UNIFESPinstname:Universidade Federal de São Paulo (UNIFESP)instacron:UNIFESP2024-08-01T00:50:30Zoai:repositorio.unifesp.br/:11600/34822Repositório InstitucionalPUBhttp://www.repositorio.unifesp.br/oai/requestbiblioteca.csp@unifesp.bropendoar:34652024-08-01T00:50:30Repositório Institucional da UNIFESP - Universidade Federal de São Paulo (UNIFESP)false
dc.title.none.fl_str_mv Effect of Natural Polymorphisms in the HIV-1 CRF02_AG Protease on Protease Inhibitor Hypersusceptibility
title Effect of Natural Polymorphisms in the HIV-1 CRF02_AG Protease on Protease Inhibitor Hypersusceptibility
spellingShingle Effect of Natural Polymorphisms in the HIV-1 CRF02_AG Protease on Protease Inhibitor Hypersusceptibility
Santos, Andre F. A.
title_short Effect of Natural Polymorphisms in the HIV-1 CRF02_AG Protease on Protease Inhibitor Hypersusceptibility
title_full Effect of Natural Polymorphisms in the HIV-1 CRF02_AG Protease on Protease Inhibitor Hypersusceptibility
title_fullStr Effect of Natural Polymorphisms in the HIV-1 CRF02_AG Protease on Protease Inhibitor Hypersusceptibility
title_full_unstemmed Effect of Natural Polymorphisms in the HIV-1 CRF02_AG Protease on Protease Inhibitor Hypersusceptibility
title_sort Effect of Natural Polymorphisms in the HIV-1 CRF02_AG Protease on Protease Inhibitor Hypersusceptibility
author Santos, Andre F. A.
author_facet Santos, Andre F. A.
Tebit, Denis M.
Lalonde, Matthew S.
Abecasis, Ana B.
Ratcliff, Annette
Camacho, Ricardo J.
Diaz, Ricardo S. [UNIFESP]
Herchenroeder, Ottmar
Soares, Marcelo A.
Arts, Eric J.
author_role author
author2 Tebit, Denis M.
Lalonde, Matthew S.
Abecasis, Ana B.
Ratcliff, Annette
Camacho, Ricardo J.
Diaz, Ricardo S. [UNIFESP]
Herchenroeder, Ottmar
Soares, Marcelo A.
Arts, Eric J.
author2_role author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Case Western Reserve Univ
Universidade Federal do Rio de Janeiro (UFRJ)
Hosp Egas Moniz
Universidade Federal de São Paulo (UNIFESP)
Univ Rostock
Inst Nacl Canc
dc.contributor.author.fl_str_mv Santos, Andre F. A.
Tebit, Denis M.
Lalonde, Matthew S.
Abecasis, Ana B.
Ratcliff, Annette
Camacho, Ricardo J.
Diaz, Ricardo S. [UNIFESP]
Herchenroeder, Ottmar
Soares, Marcelo A.
Arts, Eric J.
description Hypersusceptibility (HS) to inhibition by different antiretroviral drugs (ARVs) among diverse HIV-infected individuals may be a misnomer because clinical response to treatment is evaluated in relation to subtype B infections while drug susceptibility of the infecting virus, regardless of subtype, is compared to a subtype B HIV-1 laboratory strain (NL4-3 or IIIB). Mounting evidence suggests that HS to different ARVs may result in better treatment outcome just as drug resistance leads to treatment failure. We have identified key amino acid polymorphisms in the protease coding region of a non-B HIV-1 subtype linked to protease inhibitor HS, namely, 17E and 64M in CRF02_AG. These HS-linked polymorphisms were introduced in the BD6-15 CRF02_AG molecular clone and tested for inhibition using a panel of protease inhibitors. in general, suspected HS-linked polymorphisms did increase susceptibility to specific protease inhibitors such as amprenavir and atazanavir, but the combination of the 17E/64M polymorphisms showed greater HS. These two mutations were found at low frequencies but linked in a sequence database of over 700 protease sequences of CRF02_AG. in direct head-to-head virus competitions, CRF02_AG harboring the 17E/64M polymorphisms also had higher replicative fitness than did the 17E or the 64M polymorphism in the CFR02_AG clone. These findings suggest that subtype-specific, linked polymorphisms can result in hypersusceptibility to ARVs. Considering the potential benefit of HS to treatment outcome, screening for potential HS-linked polymorphisms as well as preexisting drug resistance mutations in treatment-naive patients may guide the choice of ARVs for the best treatment outcome.
publishDate 2012
dc.date.none.fl_str_mv 2012-05-01
2016-01-24T14:27:09Z
2016-01-24T14:27:09Z
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://dx.doi.org/10.1128/AAC.06079-11
Antimicrobial Agents and Chemotherapy. Washington: Amer Soc Microbiology, v. 56, n. 5, p. 2719-2725, 2012.
10.1128/AAC.06079-11
WOS000302790400069.pdf
0066-4804
http://repositorio.unifesp.br/handle/11600/34822
WOS:000302790400069
url http://dx.doi.org/10.1128/AAC.06079-11
http://repositorio.unifesp.br/handle/11600/34822
identifier_str_mv Antimicrobial Agents and Chemotherapy. Washington: Amer Soc Microbiology, v. 56, n. 5, p. 2719-2725, 2012.
10.1128/AAC.06079-11
WOS000302790400069.pdf
0066-4804
WOS:000302790400069
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv Antimicrobial Agents and Chemotherapy
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 2719-2725
application/pdf
dc.publisher.none.fl_str_mv Amer Soc Microbiology
publisher.none.fl_str_mv Amer Soc Microbiology
dc.source.none.fl_str_mv reponame:Repositório Institucional da UNIFESP
instname:Universidade Federal de São Paulo (UNIFESP)
instacron:UNIFESP
instname_str Universidade Federal de São Paulo (UNIFESP)
instacron_str UNIFESP
institution UNIFESP
reponame_str Repositório Institucional da UNIFESP
collection Repositório Institucional da UNIFESP
repository.name.fl_str_mv Repositório Institucional da UNIFESP - Universidade Federal de São Paulo (UNIFESP)
repository.mail.fl_str_mv biblioteca.csp@unifesp.br
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