Transient antiretroviral therapy selecting for common HIV-1 mutations substantially accelerates the appearance of rare mutations

Background Highly selective antiretroviral (ARV) regimens such as single dose nevirapine (NVP) used for prevention of mother to child transmission (PMTCT) in resource-limited settings produce transient increases in otherwise marginal subpopulations of cells infected by mutant genomes. The longer ter...
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Autor*in:	Shiri, Tinevimbo [verfasserIn] Welte, Alex

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2008

Schlagwörter:	Human Immunodeficiency Virus Infected Cell Virologic Failure Rare Mutant Viral Evolution

Anmerkung:	© Shiri and Welte; licensee BioMed Central Ltd. 2008

Übergeordnetes Werk:	Enthalten in: Theoretical biology and medical modelling - London : BioMed Central, 2004, 5(2008), 1 vom: 14. Nov.
Übergeordnetes Werk:	volume:5 ; year:2008 ; number:1 ; day:14 ; month:11

Links:	Volltext

DOI / URN:	10.1186/1742-4682-5-25

Katalog-ID:	SPR029126819

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245	1	0	\|a Transient antiretroviral therapy selecting for common HIV-1 mutations substantially accelerates the appearance of rare mutations
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520			\|a Background Highly selective antiretroviral (ARV) regimens such as single dose nevirapine (NVP) used for prevention of mother to child transmission (PMTCT) in resource-limited settings produce transient increases in otherwise marginal subpopulations of cells infected by mutant genomes. The longer term implications for accumulation of further resistance mutations are not fully understood. Methods We develop a new strain-differentiated hybrid deterministic-stochastic population dynamic type model of healthy and infected cells. We explore how the transient increase in a population of cells transcribed with a common mutation (modelled deterministically), which occurs in response to a short course of monotherapy, has an impact on the risk of appearance of rarer, higher-order, therapy-defeating mutations (modelled stochastically). Results Scenarios with a transient of a magnitude and duration such as is known to occur under NVP monotherapy exhibit significantly accelerated viral evolution compared to no-treatment scenarios. We identify a possibly important new biological timescale; namely, the duration of persistence, after a seminal mutation, of a sub-population of cells bearing the new mutant gene, and we show how increased persistence leads to an increased probability that a rare mutant will be present at the moment at which a new treatment regimen is initiated. Conclusion Even transient increases in subpopulations of common mutants are associated with accelerated appearance of further rarer mutations. Experimental data on the persistence of small subpopulations of rare mutants, in unfavourable environments, should be sought, as this affects the risk of subverting later regimens.
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allfields	10.1186/1742-4682-5-25 doi (DE-627)SPR029126819 (SPR)1742-4682-5-25-e DE-627 ger DE-627 rakwb eng Shiri, Tinevimbo verfasserin aut Transient antiretroviral therapy selecting for common HIV-1 mutations substantially accelerates the appearance of rare mutations 2008 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Shiri and Welte; licensee BioMed Central Ltd. 2008 Background Highly selective antiretroviral (ARV) regimens such as single dose nevirapine (NVP) used for prevention of mother to child transmission (PMTCT) in resource-limited settings produce transient increases in otherwise marginal subpopulations of cells infected by mutant genomes. The longer term implications for accumulation of further resistance mutations are not fully understood. Methods We develop a new strain-differentiated hybrid deterministic-stochastic population dynamic type model of healthy and infected cells. We explore how the transient increase in a population of cells transcribed with a common mutation (modelled deterministically), which occurs in response to a short course of monotherapy, has an impact on the risk of appearance of rarer, higher-order, therapy-defeating mutations (modelled stochastically). Results Scenarios with a transient of a magnitude and duration such as is known to occur under NVP monotherapy exhibit significantly accelerated viral evolution compared to no-treatment scenarios. We identify a possibly important new biological timescale; namely, the duration of persistence, after a seminal mutation, of a sub-population of cells bearing the new mutant gene, and we show how increased persistence leads to an increased probability that a rare mutant will be present at the moment at which a new treatment regimen is initiated. Conclusion Even transient increases in subpopulations of common mutants are associated with accelerated appearance of further rarer mutations. Experimental data on the persistence of small subpopulations of rare mutants, in unfavourable environments, should be sought, as this affects the risk of subverting later regimens. Human Immunodeficiency Virus (dpeaa)DE-He213 Infected Cell (dpeaa)DE-He213 Virologic Failure (dpeaa)DE-He213 Rare Mutant (dpeaa)DE-He213 Viral Evolution (dpeaa)DE-He213 Welte, Alex aut Enthalten in Theoretical biology and medical modelling London : BioMed Central, 2004 5(2008), 1 vom: 14. Nov. (DE-627)39178482X (DE-600)2156462-0 1742-4682 nnns volume:5 year:2008 number:1 day:14 month:11 https://dx.doi.org/10.1186/1742-4682-5-25 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 5 2008 1 14 11
spelling	10.1186/1742-4682-5-25 doi (DE-627)SPR029126819 (SPR)1742-4682-5-25-e DE-627 ger DE-627 rakwb eng Shiri, Tinevimbo verfasserin aut Transient antiretroviral therapy selecting for common HIV-1 mutations substantially accelerates the appearance of rare mutations 2008 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Shiri and Welte; licensee BioMed Central Ltd. 2008 Background Highly selective antiretroviral (ARV) regimens such as single dose nevirapine (NVP) used for prevention of mother to child transmission (PMTCT) in resource-limited settings produce transient increases in otherwise marginal subpopulations of cells infected by mutant genomes. The longer term implications for accumulation of further resistance mutations are not fully understood. Methods We develop a new strain-differentiated hybrid deterministic-stochastic population dynamic type model of healthy and infected cells. We explore how the transient increase in a population of cells transcribed with a common mutation (modelled deterministically), which occurs in response to a short course of monotherapy, has an impact on the risk of appearance of rarer, higher-order, therapy-defeating mutations (modelled stochastically). Results Scenarios with a transient of a magnitude and duration such as is known to occur under NVP monotherapy exhibit significantly accelerated viral evolution compared to no-treatment scenarios. We identify a possibly important new biological timescale; namely, the duration of persistence, after a seminal mutation, of a sub-population of cells bearing the new mutant gene, and we show how increased persistence leads to an increased probability that a rare mutant will be present at the moment at which a new treatment regimen is initiated. Conclusion Even transient increases in subpopulations of common mutants are associated with accelerated appearance of further rarer mutations. Experimental data on the persistence of small subpopulations of rare mutants, in unfavourable environments, should be sought, as this affects the risk of subverting later regimens. Human Immunodeficiency Virus (dpeaa)DE-He213 Infected Cell (dpeaa)DE-He213 Virologic Failure (dpeaa)DE-He213 Rare Mutant (dpeaa)DE-He213 Viral Evolution (dpeaa)DE-He213 Welte, Alex aut Enthalten in Theoretical biology and medical modelling London : BioMed Central, 2004 5(2008), 1 vom: 14. Nov. (DE-627)39178482X (DE-600)2156462-0 1742-4682 nnns volume:5 year:2008 number:1 day:14 month:11 https://dx.doi.org/10.1186/1742-4682-5-25 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 5 2008 1 14 11
allfields_unstemmed	10.1186/1742-4682-5-25 doi (DE-627)SPR029126819 (SPR)1742-4682-5-25-e DE-627 ger DE-627 rakwb eng Shiri, Tinevimbo verfasserin aut Transient antiretroviral therapy selecting for common HIV-1 mutations substantially accelerates the appearance of rare mutations 2008 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Shiri and Welte; licensee BioMed Central Ltd. 2008 Background Highly selective antiretroviral (ARV) regimens such as single dose nevirapine (NVP) used for prevention of mother to child transmission (PMTCT) in resource-limited settings produce transient increases in otherwise marginal subpopulations of cells infected by mutant genomes. The longer term implications for accumulation of further resistance mutations are not fully understood. Methods We develop a new strain-differentiated hybrid deterministic-stochastic population dynamic type model of healthy and infected cells. We explore how the transient increase in a population of cells transcribed with a common mutation (modelled deterministically), which occurs in response to a short course of monotherapy, has an impact on the risk of appearance of rarer, higher-order, therapy-defeating mutations (modelled stochastically). Results Scenarios with a transient of a magnitude and duration such as is known to occur under NVP monotherapy exhibit significantly accelerated viral evolution compared to no-treatment scenarios. We identify a possibly important new biological timescale; namely, the duration of persistence, after a seminal mutation, of a sub-population of cells bearing the new mutant gene, and we show how increased persistence leads to an increased probability that a rare mutant will be present at the moment at which a new treatment regimen is initiated. Conclusion Even transient increases in subpopulations of common mutants are associated with accelerated appearance of further rarer mutations. Experimental data on the persistence of small subpopulations of rare mutants, in unfavourable environments, should be sought, as this affects the risk of subverting later regimens. Human Immunodeficiency Virus (dpeaa)DE-He213 Infected Cell (dpeaa)DE-He213 Virologic Failure (dpeaa)DE-He213 Rare Mutant (dpeaa)DE-He213 Viral Evolution (dpeaa)DE-He213 Welte, Alex aut Enthalten in Theoretical biology and medical modelling London : BioMed Central, 2004 5(2008), 1 vom: 14. Nov. (DE-627)39178482X (DE-600)2156462-0 1742-4682 nnns volume:5 year:2008 number:1 day:14 month:11 https://dx.doi.org/10.1186/1742-4682-5-25 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 5 2008 1 14 11
allfieldsGer	10.1186/1742-4682-5-25 doi (DE-627)SPR029126819 (SPR)1742-4682-5-25-e DE-627 ger DE-627 rakwb eng Shiri, Tinevimbo verfasserin aut Transient antiretroviral therapy selecting for common HIV-1 mutations substantially accelerates the appearance of rare mutations 2008 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Shiri and Welte; licensee BioMed Central Ltd. 2008 Background Highly selective antiretroviral (ARV) regimens such as single dose nevirapine (NVP) used for prevention of mother to child transmission (PMTCT) in resource-limited settings produce transient increases in otherwise marginal subpopulations of cells infected by mutant genomes. The longer term implications for accumulation of further resistance mutations are not fully understood. Methods We develop a new strain-differentiated hybrid deterministic-stochastic population dynamic type model of healthy and infected cells. We explore how the transient increase in a population of cells transcribed with a common mutation (modelled deterministically), which occurs in response to a short course of monotherapy, has an impact on the risk of appearance of rarer, higher-order, therapy-defeating mutations (modelled stochastically). Results Scenarios with a transient of a magnitude and duration such as is known to occur under NVP monotherapy exhibit significantly accelerated viral evolution compared to no-treatment scenarios. We identify a possibly important new biological timescale; namely, the duration of persistence, after a seminal mutation, of a sub-population of cells bearing the new mutant gene, and we show how increased persistence leads to an increased probability that a rare mutant will be present at the moment at which a new treatment regimen is initiated. Conclusion Even transient increases in subpopulations of common mutants are associated with accelerated appearance of further rarer mutations. Experimental data on the persistence of small subpopulations of rare mutants, in unfavourable environments, should be sought, as this affects the risk of subverting later regimens. Human Immunodeficiency Virus (dpeaa)DE-He213 Infected Cell (dpeaa)DE-He213 Virologic Failure (dpeaa)DE-He213 Rare Mutant (dpeaa)DE-He213 Viral Evolution (dpeaa)DE-He213 Welte, Alex aut Enthalten in Theoretical biology and medical modelling London : BioMed Central, 2004 5(2008), 1 vom: 14. Nov. (DE-627)39178482X (DE-600)2156462-0 1742-4682 nnns volume:5 year:2008 number:1 day:14 month:11 https://dx.doi.org/10.1186/1742-4682-5-25 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 5 2008 1 14 11
allfieldsSound	10.1186/1742-4682-5-25 doi (DE-627)SPR029126819 (SPR)1742-4682-5-25-e DE-627 ger DE-627 rakwb eng Shiri, Tinevimbo verfasserin aut Transient antiretroviral therapy selecting for common HIV-1 mutations substantially accelerates the appearance of rare mutations 2008 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Shiri and Welte; licensee BioMed Central Ltd. 2008 Background Highly selective antiretroviral (ARV) regimens such as single dose nevirapine (NVP) used for prevention of mother to child transmission (PMTCT) in resource-limited settings produce transient increases in otherwise marginal subpopulations of cells infected by mutant genomes. The longer term implications for accumulation of further resistance mutations are not fully understood. Methods We develop a new strain-differentiated hybrid deterministic-stochastic population dynamic type model of healthy and infected cells. We explore how the transient increase in a population of cells transcribed with a common mutation (modelled deterministically), which occurs in response to a short course of monotherapy, has an impact on the risk of appearance of rarer, higher-order, therapy-defeating mutations (modelled stochastically). Results Scenarios with a transient of a magnitude and duration such as is known to occur under NVP monotherapy exhibit significantly accelerated viral evolution compared to no-treatment scenarios. We identify a possibly important new biological timescale; namely, the duration of persistence, after a seminal mutation, of a sub-population of cells bearing the new mutant gene, and we show how increased persistence leads to an increased probability that a rare mutant will be present at the moment at which a new treatment regimen is initiated. Conclusion Even transient increases in subpopulations of common mutants are associated with accelerated appearance of further rarer mutations. Experimental data on the persistence of small subpopulations of rare mutants, in unfavourable environments, should be sought, as this affects the risk of subverting later regimens. Human Immunodeficiency Virus (dpeaa)DE-He213 Infected Cell (dpeaa)DE-He213 Virologic Failure (dpeaa)DE-He213 Rare Mutant (dpeaa)DE-He213 Viral Evolution (dpeaa)DE-He213 Welte, Alex aut Enthalten in Theoretical biology and medical modelling London : BioMed Central, 2004 5(2008), 1 vom: 14. Nov. (DE-627)39178482X (DE-600)2156462-0 1742-4682 nnns volume:5 year:2008 number:1 day:14 month:11 https://dx.doi.org/10.1186/1742-4682-5-25 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 5 2008 1 14 11
language	English
source	Enthalten in Theoretical biology and medical modelling 5(2008), 1 vom: 14. Nov. volume:5 year:2008 number:1 day:14 month:11
sourceStr	Enthalten in Theoretical biology and medical modelling 5(2008), 1 vom: 14. Nov. volume:5 year:2008 number:1 day:14 month:11
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topic_facet	Human Immunodeficiency Virus Infected Cell Virologic Failure Rare Mutant Viral Evolution
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The longer term implications for accumulation of further resistance mutations are not fully understood. Methods We develop a new strain-differentiated hybrid deterministic-stochastic population dynamic type model of healthy and infected cells. We explore how the transient increase in a population of cells transcribed with a common mutation (modelled deterministically), which occurs in response to a short course of monotherapy, has an impact on the risk of appearance of rarer, higher-order, therapy-defeating mutations (modelled stochastically). Results Scenarios with a transient of a magnitude and duration such as is known to occur under NVP monotherapy exhibit significantly accelerated viral evolution compared to no-treatment scenarios. 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author	Shiri, Tinevimbo
spellingShingle	Shiri, Tinevimbo misc Human Immunodeficiency Virus misc Infected Cell misc Virologic Failure misc Rare Mutant misc Viral Evolution Transient antiretroviral therapy selecting for common HIV-1 mutations substantially accelerates the appearance of rare mutations
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topic_title	Transient antiretroviral therapy selecting for common HIV-1 mutations substantially accelerates the appearance of rare mutations Human Immunodeficiency Virus (dpeaa)DE-He213 Infected Cell (dpeaa)DE-He213 Virologic Failure (dpeaa)DE-He213 Rare Mutant (dpeaa)DE-He213 Viral Evolution (dpeaa)DE-He213
topic	misc Human Immunodeficiency Virus misc Infected Cell misc Virologic Failure misc Rare Mutant misc Viral Evolution
topic_unstemmed	misc Human Immunodeficiency Virus misc Infected Cell misc Virologic Failure misc Rare Mutant misc Viral Evolution
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title	Transient antiretroviral therapy selecting for common HIV-1 mutations substantially accelerates the appearance of rare mutations
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title_full	Transient antiretroviral therapy selecting for common HIV-1 mutations substantially accelerates the appearance of rare mutations
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title_sort	transient antiretroviral therapy selecting for common hiv-1 mutations substantially accelerates the appearance of rare mutations
title_auth	Transient antiretroviral therapy selecting for common HIV-1 mutations substantially accelerates the appearance of rare mutations
abstract	Background Highly selective antiretroviral (ARV) regimens such as single dose nevirapine (NVP) used for prevention of mother to child transmission (PMTCT) in resource-limited settings produce transient increases in otherwise marginal subpopulations of cells infected by mutant genomes. The longer term implications for accumulation of further resistance mutations are not fully understood. Methods We develop a new strain-differentiated hybrid deterministic-stochastic population dynamic type model of healthy and infected cells. We explore how the transient increase in a population of cells transcribed with a common mutation (modelled deterministically), which occurs in response to a short course of monotherapy, has an impact on the risk of appearance of rarer, higher-order, therapy-defeating mutations (modelled stochastically). Results Scenarios with a transient of a magnitude and duration such as is known to occur under NVP monotherapy exhibit significantly accelerated viral evolution compared to no-treatment scenarios. We identify a possibly important new biological timescale; namely, the duration of persistence, after a seminal mutation, of a sub-population of cells bearing the new mutant gene, and we show how increased persistence leads to an increased probability that a rare mutant will be present at the moment at which a new treatment regimen is initiated. Conclusion Even transient increases in subpopulations of common mutants are associated with accelerated appearance of further rarer mutations. Experimental data on the persistence of small subpopulations of rare mutants, in unfavourable environments, should be sought, as this affects the risk of subverting later regimens. © Shiri and Welte; licensee BioMed Central Ltd. 2008
abstractGer	Background Highly selective antiretroviral (ARV) regimens such as single dose nevirapine (NVP) used for prevention of mother to child transmission (PMTCT) in resource-limited settings produce transient increases in otherwise marginal subpopulations of cells infected by mutant genomes. The longer term implications for accumulation of further resistance mutations are not fully understood. Methods We develop a new strain-differentiated hybrid deterministic-stochastic population dynamic type model of healthy and infected cells. We explore how the transient increase in a population of cells transcribed with a common mutation (modelled deterministically), which occurs in response to a short course of monotherapy, has an impact on the risk of appearance of rarer, higher-order, therapy-defeating mutations (modelled stochastically). Results Scenarios with a transient of a magnitude and duration such as is known to occur under NVP monotherapy exhibit significantly accelerated viral evolution compared to no-treatment scenarios. We identify a possibly important new biological timescale; namely, the duration of persistence, after a seminal mutation, of a sub-population of cells bearing the new mutant gene, and we show how increased persistence leads to an increased probability that a rare mutant will be present at the moment at which a new treatment regimen is initiated. Conclusion Even transient increases in subpopulations of common mutants are associated with accelerated appearance of further rarer mutations. Experimental data on the persistence of small subpopulations of rare mutants, in unfavourable environments, should be sought, as this affects the risk of subverting later regimens. © Shiri and Welte; licensee BioMed Central Ltd. 2008
abstract_unstemmed	Background Highly selective antiretroviral (ARV) regimens such as single dose nevirapine (NVP) used for prevention of mother to child transmission (PMTCT) in resource-limited settings produce transient increases in otherwise marginal subpopulations of cells infected by mutant genomes. The longer term implications for accumulation of further resistance mutations are not fully understood. Methods We develop a new strain-differentiated hybrid deterministic-stochastic population dynamic type model of healthy and infected cells. We explore how the transient increase in a population of cells transcribed with a common mutation (modelled deterministically), which occurs in response to a short course of monotherapy, has an impact on the risk of appearance of rarer, higher-order, therapy-defeating mutations (modelled stochastically). Results Scenarios with a transient of a magnitude and duration such as is known to occur under NVP monotherapy exhibit significantly accelerated viral evolution compared to no-treatment scenarios. We identify a possibly important new biological timescale; namely, the duration of persistence, after a seminal mutation, of a sub-population of cells bearing the new mutant gene, and we show how increased persistence leads to an increased probability that a rare mutant will be present at the moment at which a new treatment regimen is initiated. Conclusion Even transient increases in subpopulations of common mutants are associated with accelerated appearance of further rarer mutations. Experimental data on the persistence of small subpopulations of rare mutants, in unfavourable environments, should be sought, as this affects the risk of subverting later regimens. © Shiri and Welte; licensee BioMed Central Ltd. 2008
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title_short	Transient antiretroviral therapy selecting for common HIV-1 mutations substantially accelerates the appearance of rare mutations
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Transient antiretroviral therapy selecting for common HIV-1 mutations substantially accelerates the appearance of rare mutations

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