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Identification of the Critical Sites of NNRTI-Resistance in Reverse Transcriptase of HIV-1 CRF_BC Strains

BACKGROUND: The polymorphisms involved in drug resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) in HIV-1 CRF_BC, the most prevalent HIV-1 strain in China, have been poorly characterized. RESULTS: To reveal the drug resistance mutations, we compared the gene sequences of pol reg...

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Autores principales: Huang, Yang, Li, Zhenpeng, Xing, Hui, Jiao, Yang, Ouyang, Yabo, Liao, Lingjie, Jiang, Shibo, Armstrong, Rebecca, Shao, Yiming, Ma, Liying
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3990534/
https://www.ncbi.nlm.nih.gov/pubmed/24743727
http://dx.doi.org/10.1371/journal.pone.0093804
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author Huang, Yang
Li, Zhenpeng
Xing, Hui
Jiao, Yang
Ouyang, Yabo
Liao, Lingjie
Jiang, Shibo
Armstrong, Rebecca
Shao, Yiming
Ma, Liying
author_facet Huang, Yang
Li, Zhenpeng
Xing, Hui
Jiao, Yang
Ouyang, Yabo
Liao, Lingjie
Jiang, Shibo
Armstrong, Rebecca
Shao, Yiming
Ma, Liying
author_sort Huang, Yang
collection PubMed
description BACKGROUND: The polymorphisms involved in drug resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) in HIV-1 CRF_BC, the most prevalent HIV-1 strain in China, have been poorly characterized. RESULTS: To reveal the drug resistance mutations, we compared the gene sequences of pol region of HIV-1 CRF_BC from 631 treatment-naïve and 363 treatment-experienced patients using the selection pressure-based method. We calculated an individual Ka/Ks value for each specific amino acid mutation. Result showed that eight polymorphic mutations (W88C, K101Q, I132L, R135L, T139K/R, H221Y and L228R) in RT for treatment-experienced patients were identified, while they, except for R135L, were completely absent in those from treatment-naïve patients. The I132L and T139K/R mutants exhibited high-level resistance to DLV and NVP and moderate resistance to TMC-125 and EFV, while the K101Q and H221Y mutants exhibited an increased resistance to all four NNRTIs tested. The W88C, R135L, and L228R may be RTI-induced adaptive mutations. Y181C+K101Q mutant showed a 2.5-, 4.4-, and 4.7-fold higher resistance to TMC-125, NVP and EFV, respectively, than Y181C alone mutant, while Y181C+H221Y or K103N+H221Y mutants had significantly higher resistance to all four NNRTIs than Y181C or K103N mutants. K103N+T139K and G190A+T139K mutant induce higher resistance (2.0∼14.2-fold and 1.5∼7.2-fold, respectively) to all four NNRTIs than K103N or G190A alone mutation. CONCLUSIONS: I132L and T139K/R are rare but critical mutations associated with NNRTI-resistance for some NNRTIs. K101Q, H221Y and T139K can enhance K103N/Y181C/G190A-assocated NNRTI-resistance. Monitoring these mutations will provide useful information for rational design of the NNRTI-based antiretroviral regimen for HIV-1 CRF_BC-infected patients.
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spelling pubmed-39905342014-04-21 Identification of the Critical Sites of NNRTI-Resistance in Reverse Transcriptase of HIV-1 CRF_BC Strains Huang, Yang Li, Zhenpeng Xing, Hui Jiao, Yang Ouyang, Yabo Liao, Lingjie Jiang, Shibo Armstrong, Rebecca Shao, Yiming Ma, Liying PLoS One Research Article BACKGROUND: The polymorphisms involved in drug resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) in HIV-1 CRF_BC, the most prevalent HIV-1 strain in China, have been poorly characterized. RESULTS: To reveal the drug resistance mutations, we compared the gene sequences of pol region of HIV-1 CRF_BC from 631 treatment-naïve and 363 treatment-experienced patients using the selection pressure-based method. We calculated an individual Ka/Ks value for each specific amino acid mutation. Result showed that eight polymorphic mutations (W88C, K101Q, I132L, R135L, T139K/R, H221Y and L228R) in RT for treatment-experienced patients were identified, while they, except for R135L, were completely absent in those from treatment-naïve patients. The I132L and T139K/R mutants exhibited high-level resistance to DLV and NVP and moderate resistance to TMC-125 and EFV, while the K101Q and H221Y mutants exhibited an increased resistance to all four NNRTIs tested. The W88C, R135L, and L228R may be RTI-induced adaptive mutations. Y181C+K101Q mutant showed a 2.5-, 4.4-, and 4.7-fold higher resistance to TMC-125, NVP and EFV, respectively, than Y181C alone mutant, while Y181C+H221Y or K103N+H221Y mutants had significantly higher resistance to all four NNRTIs than Y181C or K103N mutants. K103N+T139K and G190A+T139K mutant induce higher resistance (2.0∼14.2-fold and 1.5∼7.2-fold, respectively) to all four NNRTIs than K103N or G190A alone mutation. CONCLUSIONS: I132L and T139K/R are rare but critical mutations associated with NNRTI-resistance for some NNRTIs. K101Q, H221Y and T139K can enhance K103N/Y181C/G190A-assocated NNRTI-resistance. Monitoring these mutations will provide useful information for rational design of the NNRTI-based antiretroviral regimen for HIV-1 CRF_BC-infected patients. Public Library of Science 2014-04-17 /pmc/articles/PMC3990534/ /pubmed/24743727 http://dx.doi.org/10.1371/journal.pone.0093804 Text en © 2014 Huang et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Huang, Yang
Li, Zhenpeng
Xing, Hui
Jiao, Yang
Ouyang, Yabo
Liao, Lingjie
Jiang, Shibo
Armstrong, Rebecca
Shao, Yiming
Ma, Liying
Identification of the Critical Sites of NNRTI-Resistance in Reverse Transcriptase of HIV-1 CRF_BC Strains
title Identification of the Critical Sites of NNRTI-Resistance in Reverse Transcriptase of HIV-1 CRF_BC Strains
title_full Identification of the Critical Sites of NNRTI-Resistance in Reverse Transcriptase of HIV-1 CRF_BC Strains
title_fullStr Identification of the Critical Sites of NNRTI-Resistance in Reverse Transcriptase of HIV-1 CRF_BC Strains
title_full_unstemmed Identification of the Critical Sites of NNRTI-Resistance in Reverse Transcriptase of HIV-1 CRF_BC Strains
title_short Identification of the Critical Sites of NNRTI-Resistance in Reverse Transcriptase of HIV-1 CRF_BC Strains
title_sort identification of the critical sites of nnrti-resistance in reverse transcriptase of hiv-1 crf_bc strains
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3990534/
https://www.ncbi.nlm.nih.gov/pubmed/24743727
http://dx.doi.org/10.1371/journal.pone.0093804
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