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Statements

Subject Item
n2:RIV%2F61388963%3A_____%2F13%3A00394764%21RIV14-MSM-61388963
rdf:type
skos:Concept n9:Vysledek
rdfs:seeAlso
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0065631
dcterms:description
Most studies describing phenotypic resistance to integrase strand transfer inhibitors have analyzed viruses carrying only patient-derived HIV-1 integrase genes (INT-recombinant viruses). However, to date, many of the patients on INSTI-based treatment regimes, such as raltegravir (RAL), elvitegravir (EVG), and dolutegravir (DTG) are infected with multidrug-resistant HIV-1 strains. Here we analyzed the effect of drug resistance mutations in Gag (p2/NCp7/p1/p6), protease (PR), reverse transcriptase (RT), and integrase (IN) coding regions on susceptibility to INSTIs and viral replicative fitness using a novel HIV-1 phenotyping assay. Two sets of recombinant viruses containing a 3,428-bp gag-p2/NCp7/p1/p6/pol-PR/RT/IN (p2-INT) or a 1,088 bp integrase (INT) patient-derived fragment were constructed from plasma samples obtained from 27 virologic failure patients participating in a 48-week dose-ranging study of elvitegravir, GS-US-183-0105. A strong correlation was observed when susceptibility to EVG and RAL was assayed using p2-INT-vs. INT-recombinant viruses (Pearson coefficient correlation 0.869 and 0.918, P<0.0001 for EVG and RAL, respectively), demonstrating that mutations in the protease and RT have limited effect on susceptibility to these INSTIs. On the other hand, the replicative fitness of viruses harboring drug resistance mutations in PR, RT, and IN was generally impaired compared to viruses carrying only INSTI-resistance mutations. Thus, in the absence of drug pressure, drug resistance mutations in the PR and RT contribute to decrease the replicative fitness of the virus already impaired by mutations in the integrase. The use of recombinant viruses containing most or all HIV-1 regions targeted by antiretroviral drugs might be essential to understand the collective effect of epistatic interactions in multidrug-resistant viruses. Most studies describing phenotypic resistance to integrase strand transfer inhibitors have analyzed viruses carrying only patient-derived HIV-1 integrase genes (INT-recombinant viruses). However, to date, many of the patients on INSTI-based treatment regimes, such as raltegravir (RAL), elvitegravir (EVG), and dolutegravir (DTG) are infected with multidrug-resistant HIV-1 strains. Here we analyzed the effect of drug resistance mutations in Gag (p2/NCp7/p1/p6), protease (PR), reverse transcriptase (RT), and integrase (IN) coding regions on susceptibility to INSTIs and viral replicative fitness using a novel HIV-1 phenotyping assay. Two sets of recombinant viruses containing a 3,428-bp gag-p2/NCp7/p1/p6/pol-PR/RT/IN (p2-INT) or a 1,088 bp integrase (INT) patient-derived fragment were constructed from plasma samples obtained from 27 virologic failure patients participating in a 48-week dose-ranging study of elvitegravir, GS-US-183-0105. A strong correlation was observed when susceptibility to EVG and RAL was assayed using p2-INT-vs. INT-recombinant viruses (Pearson coefficient correlation 0.869 and 0.918, P<0.0001 for EVG and RAL, respectively), demonstrating that mutations in the protease and RT have limited effect on susceptibility to these INSTIs. On the other hand, the replicative fitness of viruses harboring drug resistance mutations in PR, RT, and IN was generally impaired compared to viruses carrying only INSTI-resistance mutations. Thus, in the absence of drug pressure, drug resistance mutations in the PR and RT contribute to decrease the replicative fitness of the virus already impaired by mutations in the integrase. The use of recombinant viruses containing most or all HIV-1 regions targeted by antiretroviral drugs might be essential to understand the collective effect of epistatic interactions in multidrug-resistant viruses.
dcterms:title
Resistance Mutations outside the Integrase Coding Region Have an Effect on Human Immunodeficiency Virus Replicative Fitness but Do Not Affect Its Susceptibility to Integrase Strand Transfer Inhibitors Resistance Mutations outside the Integrase Coding Region Have an Effect on Human Immunodeficiency Virus Replicative Fitness but Do Not Affect Its Susceptibility to Integrase Strand Transfer Inhibitors
skos:prefLabel
Resistance Mutations outside the Integrase Coding Region Have an Effect on Human Immunodeficiency Virus Replicative Fitness but Do Not Affect Its Susceptibility to Integrase Strand Transfer Inhibitors Resistance Mutations outside the Integrase Coding Region Have an Effect on Human Immunodeficiency Virus Replicative Fitness but Do Not Affect Its Susceptibility to Integrase Strand Transfer Inhibitors
skos:notation
RIV/61388963:_____/13:00394764!RIV14-MSM-61388963
n9:predkladatel
n20:ico%3A61388963
n3:aktivita
n15:I n15:P
n3:aktivity
I, P(LK11207)
n3:cisloPeriodika
6
n3:dodaniDat
n6:2014
n3:domaciTvurceVysledku
n17:3380351
n3:druhVysledku
n13:J
n3:duvernostUdaju
n19:S
n3:entitaPredkladatele
n18:predkladatel
n3:idSjednocenehoVysledku
102596
n3:idVysledku
RIV/61388963:_____/13:00394764
n3:jazykVysledku
n14:eng
n3:klicovaSlova
HIV-1 reverse-transcriptase; viral fitness; antiretroviral therapy; clinical-implications
n3:klicoveSlovo
n10:clinical-implications n10:antiretroviral%20therapy n10:HIV-1%20reverse-transcriptase n10:viral%20fitness
n3:kodStatuVydavatele
US - Spojené státy americké
n3:kontrolniKodProRIV
[08533269BBD8]
n3:nazevZdroje
PLoS ONE
n3:obor
n16:EE
n3:pocetDomacichTvurcuVysledku
1
n3:pocetTvurcuVysledku
8
n3:projekt
n4:LK11207
n3:rokUplatneniVysledku
n6:2013
n3:svazekPeriodika
8
n3:tvurceVysledku
Vazquez, A. C. Weber, Jan Winner, D. McColl, D. J. Margot, N. Quinones-Mateu, M. E. Rose, J. D. Miller, M. D.
n3:wos
000320755400049
s:issn
1932-6203
s:numberOfPages
14
n11:doi
10.1371/journal.pone.0065631