Suppression of Drug Resistance in Dengue Virus

ABSTRACT Dengue virus is a major human pathogen responsible for 400 million infections yearly. As with other RNA viruses, daunting challenges to antiviral design exist due to the high error rates of RNA-dependent RNA synthesis. Indeed, treatment of dengue virus infection with a nucleoside analog res...

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Autores principales:	Roberto Mateo, Claude M. Nagamine, Karla Kirkegaard
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2015
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/fca0a1a02dcf4272b992bde8f4d1ca32
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spelling	oai:doaj.org-article:fca0a1a02dcf4272b992bde8f4d1ca322021-11-15T15:41:22ZSuppression of Drug Resistance in Dengue Virus10.1128/mBio.01960-152150-7511https://doaj.org/article/fca0a1a02dcf4272b992bde8f4d1ca322015-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01960-15https://doaj.org/toc/2150-7511ABSTRACT Dengue virus is a major human pathogen responsible for 400 million infections yearly. As with other RNA viruses, daunting challenges to antiviral design exist due to the high error rates of RNA-dependent RNA synthesis. Indeed, treatment of dengue virus infection with a nucleoside analog resulted in the expected genetic selection of resistant viruses in tissue culture and in mice. However, when the function of the oligomeric core protein was inhibited, no detectable selection of drug resistance in tissue culture or in mice was detected, despite the presence of drug-resistant variants in the population. Suppressed selection of drug-resistant virus correlated with cooligomerization of the targeted drug-susceptible and drug-resistant core proteins. The concept of “dominant drug targets,” in which inhibition of oligomeric viral assemblages leads to the formation of drug-susceptible chimeras, can therefore be used to prevent the outgrowth of drug resistance during dengue virus infection. IMPORTANCE Drug resistance is a major hurdle in the development of effective antivirals, especially those directed at RNA viruses. We have found that one can use the concept of the genetic dominance of defective subunits to “turn cousins into enemies,” i.e., to thwart the outgrowth of drug-resistant viral genomes as soon as they are generated. This requires deliberate targeting of larger assemblages, which would otherwise rarely be considered by antiviral researchers.Roberto MateoClaude M. NagamineKarla KirkegaardAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 6, Iss 6 (2015)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Roberto Mateo Claude M. Nagamine Karla Kirkegaard Suppression of Drug Resistance in Dengue Virus
description	ABSTRACT Dengue virus is a major human pathogen responsible for 400 million infections yearly. As with other RNA viruses, daunting challenges to antiviral design exist due to the high error rates of RNA-dependent RNA synthesis. Indeed, treatment of dengue virus infection with a nucleoside analog resulted in the expected genetic selection of resistant viruses in tissue culture and in mice. However, when the function of the oligomeric core protein was inhibited, no detectable selection of drug resistance in tissue culture or in mice was detected, despite the presence of drug-resistant variants in the population. Suppressed selection of drug-resistant virus correlated with cooligomerization of the targeted drug-susceptible and drug-resistant core proteins. The concept of “dominant drug targets,” in which inhibition of oligomeric viral assemblages leads to the formation of drug-susceptible chimeras, can therefore be used to prevent the outgrowth of drug resistance during dengue virus infection. IMPORTANCE Drug resistance is a major hurdle in the development of effective antivirals, especially those directed at RNA viruses. We have found that one can use the concept of the genetic dominance of defective subunits to “turn cousins into enemies,” i.e., to thwart the outgrowth of drug-resistant viral genomes as soon as they are generated. This requires deliberate targeting of larger assemblages, which would otherwise rarely be considered by antiviral researchers.
format	article
author	Roberto Mateo Claude M. Nagamine Karla Kirkegaard
author_facet	Roberto Mateo Claude M. Nagamine Karla Kirkegaard
author_sort	Roberto Mateo
title	Suppression of Drug Resistance in Dengue Virus
title_short	Suppression of Drug Resistance in Dengue Virus
title_full	Suppression of Drug Resistance in Dengue Virus
title_fullStr	Suppression of Drug Resistance in Dengue Virus
title_full_unstemmed	Suppression of Drug Resistance in Dengue Virus
title_sort	suppression of drug resistance in dengue virus
publisher	American Society for Microbiology
publishDate	2015
url	https://doaj.org/article/fca0a1a02dcf4272b992bde8f4d1ca32
work_keys_str_mv	AT robertomateo suppressionofdrugresistanceindenguevirus AT claudemnagamine suppressionofdrugresistanceindenguevirus AT karlakirkegaard suppressionofdrugresistanceindenguevirus
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Suppression of Drug Resistance in Dengue Virus

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