Effect of Natural Polymorphisms in the HIV-1 CRF02_AG Protease on Protease Inhibitor Hypersusceptibility
Autor(a) principal: | |
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Data de Publicação: | 2012 |
Outros Autores: | , , , , , , , , |
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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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 |
_version_ |
1814268367174893568 |