Comparing mutational pathways to lopinavir resistance in HIV-1 subtypes B versus C.

Although combination antiretroviral therapies seem to be effective at controlling HIV-1 infections regardless of the viral subtype, there is increasing evidence for subtype-specific drug resistance mutations. The order and rates at which resistance mutations accumulate in different subtypes also rem...

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Autores principales:	Susana Posada-Céspedes, Gert Van Zyl, Hesam Montazeri, Jack Kuipers, Soo-Yon Rhee, Roger Kouyos, Huldrych F Günthard, Niko Beerenwinkel
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/234cad3e39d142a49b86b6057a9e52e3
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spelling	oai:doaj.org-article:234cad3e39d142a49b86b6057a9e52e32021-12-02T19:57:51ZComparing mutational pathways to lopinavir resistance in HIV-1 subtypes B versus C.1553-734X1553-735810.1371/journal.pcbi.1008363https://doaj.org/article/234cad3e39d142a49b86b6057a9e52e32021-09-01T00:00:00Zhttps://doi.org/10.1371/journal.pcbi.1008363https://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358Although combination antiretroviral therapies seem to be effective at controlling HIV-1 infections regardless of the viral subtype, there is increasing evidence for subtype-specific drug resistance mutations. The order and rates at which resistance mutations accumulate in different subtypes also remain poorly understood. Most of this knowledge is derived from studies of subtype B genotypes, despite not being the most abundant subtype worldwide. Here, we present a methodology for the comparison of mutational networks in different HIV-1 subtypes, based on Hidden Conjunctive Bayesian Networks (H-CBN), a probabilistic model for inferring mutational networks from cross-sectional genotype data. We introduce a Monte Carlo sampling scheme for learning H-CBN models for a larger number of resistance mutations and develop a statistical test to assess differences in the inferred mutational networks between two groups. We apply this method to infer the temporal progression of mutations conferring resistance to the protease inhibitor lopinavir in a large cross-sectional cohort of HIV-1 subtype C genotypes from South Africa, as well as to a data set of subtype B genotypes obtained from the Stanford HIV Drug Resistance Database and the Swiss HIV Cohort Study. We find strong support for different initial mutational events in the protease, namely at residue 46 in subtype B and at residue 82 in subtype C. The inferred mutational networks for subtype B versus C are significantly different sharing only five constraints on the order of accumulating mutations with mutation at residue 54 as the parental event. The results also suggest that mutations can accumulate along various alternative paths within subtypes, as opposed to a unique total temporal ordering. Beyond HIV drug resistance, the statistical methodology is applicable more generally for the comparison of inferred mutational networks between any two groups.Susana Posada-CéspedesGert Van ZylHesam MontazeriJack KuipersSoo-Yon RheeRoger KouyosHuldrych F GünthardNiko BeerenwinkelPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 17, Iss 9, p e1008363 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Susana Posada-Céspedes Gert Van Zyl Hesam Montazeri Jack Kuipers Soo-Yon Rhee Roger Kouyos Huldrych F Günthard Niko Beerenwinkel Comparing mutational pathways to lopinavir resistance in HIV-1 subtypes B versus C.
description	Although combination antiretroviral therapies seem to be effective at controlling HIV-1 infections regardless of the viral subtype, there is increasing evidence for subtype-specific drug resistance mutations. The order and rates at which resistance mutations accumulate in different subtypes also remain poorly understood. Most of this knowledge is derived from studies of subtype B genotypes, despite not being the most abundant subtype worldwide. Here, we present a methodology for the comparison of mutational networks in different HIV-1 subtypes, based on Hidden Conjunctive Bayesian Networks (H-CBN), a probabilistic model for inferring mutational networks from cross-sectional genotype data. We introduce a Monte Carlo sampling scheme for learning H-CBN models for a larger number of resistance mutations and develop a statistical test to assess differences in the inferred mutational networks between two groups. We apply this method to infer the temporal progression of mutations conferring resistance to the protease inhibitor lopinavir in a large cross-sectional cohort of HIV-1 subtype C genotypes from South Africa, as well as to a data set of subtype B genotypes obtained from the Stanford HIV Drug Resistance Database and the Swiss HIV Cohort Study. We find strong support for different initial mutational events in the protease, namely at residue 46 in subtype B and at residue 82 in subtype C. The inferred mutational networks for subtype B versus C are significantly different sharing only five constraints on the order of accumulating mutations with mutation at residue 54 as the parental event. The results also suggest that mutations can accumulate along various alternative paths within subtypes, as opposed to a unique total temporal ordering. Beyond HIV drug resistance, the statistical methodology is applicable more generally for the comparison of inferred mutational networks between any two groups.
format	article
author	Susana Posada-Céspedes Gert Van Zyl Hesam Montazeri Jack Kuipers Soo-Yon Rhee Roger Kouyos Huldrych F Günthard Niko Beerenwinkel
author_facet	Susana Posada-Céspedes Gert Van Zyl Hesam Montazeri Jack Kuipers Soo-Yon Rhee Roger Kouyos Huldrych F Günthard Niko Beerenwinkel
author_sort	Susana Posada-Céspedes
title	Comparing mutational pathways to lopinavir resistance in HIV-1 subtypes B versus C.
title_short	Comparing mutational pathways to lopinavir resistance in HIV-1 subtypes B versus C.
title_full	Comparing mutational pathways to lopinavir resistance in HIV-1 subtypes B versus C.
title_fullStr	Comparing mutational pathways to lopinavir resistance in HIV-1 subtypes B versus C.
title_full_unstemmed	Comparing mutational pathways to lopinavir resistance in HIV-1 subtypes B versus C.
title_sort	comparing mutational pathways to lopinavir resistance in hiv-1 subtypes b versus c.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/234cad3e39d142a49b86b6057a9e52e3
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Comparing mutational pathways to lopinavir resistance in HIV-1 subtypes B versus C.

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