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In Vitro HIV-1 Evolution in Response to Triple Reverse Transcriptase Inhibitors & In Silico Phenotypic Analysis

BACKGROUND: Effectiveness of ART regimens strongly depends upon complex interactions between the selective pressure of drugs and the evolution of mutations that allow or restrict drug resistance. METHODS: Four clinical isolates from NRTI-exposed, NNRTI-naive subjects were passaged in increasing conc...

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Autores principales: Rath, Barbara A., Yousef, Kaveh Pouran, Katzenstein, David K., Shafer, Robert W., Schütte, Christof, von Kleist, Max, Merigan, Thomas C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3629221/
https://www.ncbi.nlm.nih.gov/pubmed/23613794
http://dx.doi.org/10.1371/journal.pone.0061102
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author Rath, Barbara A.
Yousef, Kaveh Pouran
Katzenstein, David K.
Shafer, Robert W.
Schütte, Christof
von Kleist, Max
Merigan, Thomas C.
author_facet Rath, Barbara A.
Yousef, Kaveh Pouran
Katzenstein, David K.
Shafer, Robert W.
Schütte, Christof
von Kleist, Max
Merigan, Thomas C.
author_sort Rath, Barbara A.
collection PubMed
description BACKGROUND: Effectiveness of ART regimens strongly depends upon complex interactions between the selective pressure of drugs and the evolution of mutations that allow or restrict drug resistance. METHODS: Four clinical isolates from NRTI-exposed, NNRTI-naive subjects were passaged in increasing concentrations of NVP in combination with 1 µM 3 TC and 2 µM ADV to assess selective pressures of multi-drug treatment. A novel parameter inference procedure, based on a stochastic viral growth model, was used to estimate phenotypic resistance and fitness from in vitro combination passage experiments. RESULTS: Newly developed mathematical methods estimated key phenotypic parameters of mutations arising through selective pressure exerted by 3 TC and NVP. Concentrations of 1 µM 3 TC maintained the M184V mutation, which was associated with intrinsic fitness deficits. Increasing NVP concentrations selected major NNRTI resistance mutations. The evolutionary pathway of NVP resistance was highly dependent on the viral genetic background, epistasis as well as stochasticity. Parameter estimation indicated that the previously unrecognized mutation L228Q was associated with NVP resistance in some isolates. CONCLUSION: Serial passage of viruses in the presence of multiple drugs may resemble the selection of mutations observed among treated individuals and populations in vivo and indicate evolutionary preferences and restrictions. Phenotypic resistance estimated here “in silico” from in vitro passage experiments agreed well with previous knowledge, suggesting that the unique combination of “wet-” and “dry-lab” experimentation may improve our understanding of HIV-1 resistance evolution in the future.
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spelling pubmed-36292212013-04-23 In Vitro HIV-1 Evolution in Response to Triple Reverse Transcriptase Inhibitors & In Silico Phenotypic Analysis Rath, Barbara A. Yousef, Kaveh Pouran Katzenstein, David K. Shafer, Robert W. Schütte, Christof von Kleist, Max Merigan, Thomas C. PLoS One Research Article BACKGROUND: Effectiveness of ART regimens strongly depends upon complex interactions between the selective pressure of drugs and the evolution of mutations that allow or restrict drug resistance. METHODS: Four clinical isolates from NRTI-exposed, NNRTI-naive subjects were passaged in increasing concentrations of NVP in combination with 1 µM 3 TC and 2 µM ADV to assess selective pressures of multi-drug treatment. A novel parameter inference procedure, based on a stochastic viral growth model, was used to estimate phenotypic resistance and fitness from in vitro combination passage experiments. RESULTS: Newly developed mathematical methods estimated key phenotypic parameters of mutations arising through selective pressure exerted by 3 TC and NVP. Concentrations of 1 µM 3 TC maintained the M184V mutation, which was associated with intrinsic fitness deficits. Increasing NVP concentrations selected major NNRTI resistance mutations. The evolutionary pathway of NVP resistance was highly dependent on the viral genetic background, epistasis as well as stochasticity. Parameter estimation indicated that the previously unrecognized mutation L228Q was associated with NVP resistance in some isolates. CONCLUSION: Serial passage of viruses in the presence of multiple drugs may resemble the selection of mutations observed among treated individuals and populations in vivo and indicate evolutionary preferences and restrictions. Phenotypic resistance estimated here “in silico” from in vitro passage experiments agreed well with previous knowledge, suggesting that the unique combination of “wet-” and “dry-lab” experimentation may improve our understanding of HIV-1 resistance evolution in the future. Public Library of Science 2013-04-17 /pmc/articles/PMC3629221/ /pubmed/23613794 http://dx.doi.org/10.1371/journal.pone.0061102 Text en © 2013 Rath 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
Rath, Barbara A.
Yousef, Kaveh Pouran
Katzenstein, David K.
Shafer, Robert W.
Schütte, Christof
von Kleist, Max
Merigan, Thomas C.
In Vitro HIV-1 Evolution in Response to Triple Reverse Transcriptase Inhibitors & In Silico Phenotypic Analysis
title In Vitro HIV-1 Evolution in Response to Triple Reverse Transcriptase Inhibitors & In Silico Phenotypic Analysis
title_full In Vitro HIV-1 Evolution in Response to Triple Reverse Transcriptase Inhibitors & In Silico Phenotypic Analysis
title_fullStr In Vitro HIV-1 Evolution in Response to Triple Reverse Transcriptase Inhibitors & In Silico Phenotypic Analysis
title_full_unstemmed In Vitro HIV-1 Evolution in Response to Triple Reverse Transcriptase Inhibitors & In Silico Phenotypic Analysis
title_short In Vitro HIV-1 Evolution in Response to Triple Reverse Transcriptase Inhibitors & In Silico Phenotypic Analysis
title_sort in vitro hiv-1 evolution in response to triple reverse transcriptase inhibitors & in silico phenotypic analysis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3629221/
https://www.ncbi.nlm.nih.gov/pubmed/23613794
http://dx.doi.org/10.1371/journal.pone.0061102
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