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Statements

Subject Item
n2:RIV%2F61388963%3A_____%2F12%3A00377476%21RIV13-AV0-61388963
rdf:type
n5:Vysledek skos:Concept
dcterms:description
Mutations in the substrate of the HIV-1 protease, especially changes in the NC/p1 cleavage site, can act not only as compensatory mutations but can also directly contribute to protease inhibitor (PI) resistance. These NC/p1 changes bring about PI resistance by causing an enhanced processing of the Gag protein. To investigate the capacity of HIV to modulate Gag cleavage and its consequences for protease inhibitor resistance and replicative capacity (RC), we performed a detailed enzymatic and virological analysis using a set of PI resistant NC/p1 variants (HXB2436E+437T, HXB2437T, HXB2437V and HXB2431V). Here we demonstrate that single NC/p1 mutants, which displayed only a slight increase in PI resistance didn’t show an obvious change in RC. In contrast, the double NC/p1 mutant, which displayed a clear increase in processing efficiency and PI resistance, also demonstrated a clear reduction in RC. Evolution experiments revealed that this decrease in RC could be (partially) restored by either reversion of the 436E change or by the acquisition of additional changes at codon 435 or 438. Furthermore, these changes also normalized Gag processing efficiency and returned PI susceptibility in the direction of wild type level. The results of this study demonstrate that when enhanced Gag processing due to PI resistance mutations in NC/p1 reduces RC, HIV-1 can modulate the NC/p1 sequence to restore RC and Gag cleavage to an optimal rate. Mutations in the substrate of the HIV-1 protease, especially changes in the NC/p1 cleavage site, can act not only as compensatory mutations but can also directly contribute to protease inhibitor (PI) resistance. These NC/p1 changes bring about PI resistance by causing an enhanced processing of the Gag protein. To investigate the capacity of HIV to modulate Gag cleavage and its consequences for protease inhibitor resistance and replicative capacity (RC), we performed a detailed enzymatic and virological analysis using a set of PI resistant NC/p1 variants (HXB2436E+437T, HXB2437T, HXB2437V and HXB2431V). Here we demonstrate that single NC/p1 mutants, which displayed only a slight increase in PI resistance didn’t show an obvious change in RC. In contrast, the double NC/p1 mutant, which displayed a clear increase in processing efficiency and PI resistance, also demonstrated a clear reduction in RC. Evolution experiments revealed that this decrease in RC could be (partially) restored by either reversion of the 436E change or by the acquisition of additional changes at codon 435 or 438. Furthermore, these changes also normalized Gag processing efficiency and returned PI susceptibility in the direction of wild type level. The results of this study demonstrate that when enhanced Gag processing due to PI resistance mutations in NC/p1 reduces RC, HIV-1 can modulate the NC/p1 sequence to restore RC and Gag cleavage to an optimal rate.
dcterms:title
Modulation of HIV-1 Gag NC/p1 cleavage efficiency affects protease inhibitor resistance and viral replicative capacity Modulation of HIV-1 Gag NC/p1 cleavage efficiency affects protease inhibitor resistance and viral replicative capacity
skos:prefLabel
Modulation of HIV-1 Gag NC/p1 cleavage efficiency affects protease inhibitor resistance and viral replicative capacity Modulation of HIV-1 Gag NC/p1 cleavage efficiency affects protease inhibitor resistance and viral replicative capacity
skos:notation
RIV/61388963:_____/12:00377476!RIV13-AV0-61388963
n5:predkladatel
n7:ico%3A61388963
n3:aktivita
n4:Z
n3:aktivity
Z(AV0Z40550506)
n3:cisloPeriodika
29
n3:dodaniDat
n15:2013
n3:domaciTvurceVysledku
n13:5796644 Andersson, Dan
n3:druhVysledku
n17:J
n3:duvernostUdaju
n19:S
n3:entitaPredkladatele
n18:predkladatel
n3:idSjednocenehoVysledku
151481
n3:idVysledku
RIV/61388963:_____/12:00377476
n3:jazykVysledku
n16:eng
n3:klicovaSlova
HIV-1; protease; Gag; resistance; cleavage
n3:klicoveSlovo
n12:resistance n12:HIV-1 n12:protease n12:Gag n12:cleavage
n3:kodStatuVydavatele
GB - Spojené království Velké Británie a Severního Irska
n3:kontrolniKodProRIV
[36DAA30474D3]
n3:nazevZdroje
Retrovirology
n3:obor
n14:CE
n3:pocetDomacichTvurcuVysledku
2
n3:pocetTvurcuVysledku
8
n3:rokUplatneniVysledku
n15:2012
n3:svazekPeriodika
9
n3:tvurceVysledku
Lepšík, Martin Maarseveen van, N. M. Jong de, D. Fun, A. Schipper, P. J. Boucher, Ch. A. B. Nijhuis, M. Andersson, Dan
n3:wos
000303870000001
n3:zamer
n8:AV0Z40550506
s:issn
1742-4690
s:numberOfPages
7
n10:doi
10.1186/1742-4690-9-29