Comparative replication capacity of raltegravir-resistant strains and antiviral activity of the new-generation integrase inhibitor dolutegravir in human primary macrophages and lymphocytes.
PMID: 24860155
2014
The Journal of antimicrobial chemotherapy
Abstract: In C8166 (the only cell model in which replication capacity was sufficient to perform the test) dolutegravir showed full efficacy against mutations N155H + Y143C (dolutegravir fold-change resistance: 0.6) and a slightly lower activity against G140S+Q148H (dolutegravir fold-change resistance: 2.1).
Abstract: In MDMs and PBMCs, a dramatic decrease in viral replication was observed for the double mutants N155H + Y143C and G140S +
Abstract: In all cellular models analysed, dolutegravir showed full efficacy against N155H and Y143C mutants (dolutegravir fold-change resistance ranging from 0.1 to 1.4; raltegravir fold-change resistance ranging from 0.1 to 10.3).
Dolutegravir interactions with HIV-1 integrase-DNA: structural rationale for drug resistance and dissociation kinetics.
Abstract: Signature HIV-1 integrase mutations associated with clinical raltegravir resistance involve 1 of 3 primary genetic pathways, Y143C/R, Q148H/K/R and N155H, the latter 2 of which confer cross-resistance to elvitegravir.
Discussion: Dolutegravir maintains prolonged binding with the Y143C/H/R mutants as demonstrated by dissociative t1/2 values of 42 to 60 hours.
Discussion: Note, from Table S1 in File S1, however, that EVG's dissociative t1/2 values with Y143C/H/R, which range from 1.6 to 2.1 hours, are comparable in magnitude to those of RAL, yet EVG has near wild-type antiviral activity.
Discussion: The 4.4-, 3.5- and 8-fold decreases in RAL's dissociative t1/2 caused by the Y
In vitro phenotypes to elvitegravir and dolutegravir in primary macrophages and lymphocytes of clonal recombinant viral variants selected in patients failing raltegravir.
PMID: 23798668
2013
The Journal of antimicrobial chemotherapy
Abstract: No variations were observed for the Y143R/C (+/-T97A) or N155H variants.
Abstract: When compared with raltegravir, none to modest increases in resistance were observed for the Y143R/C pathways.
Binding mode prediction of biologically active compounds from plant Salvia Miltiorrhiza as integrase inhibitor.
Introduction: The two primary resistance pathways involved mutations of the amino acids at Q148 (Q148K/R/H) or N155 (N155/H) whereas a third primary mutation pathway at Y143 (Y143C/R) was less commonly found .
Discussion: The proposed raltegravir resistance pathway of the less frequently Y143H/R/C has been directly related to the interaction between inhibitor and Tyr143.
Multiple genetic pathways involving amino acid position 143 of HIV-1 integrase are preferentially associated with specific secondary amino acid substitutions and confer resistance to raltegravir and cross-resistance to elvitegravir.
PMID: 23733474
2013
Antimicrobial agents and chemotherapy
Abstract: Among Y143A,C,G,H,S viruses, the higher prevalence of Y143C viruses is the result of a lower genetic barrier than that of the Y143A,G,S viruses and a lower resistance barrier than that of the Y143H viruses.
Abstract: Here we describe clinical isolates with alternative substitutions at position 143 (Y143A, Y143G, Y143H, and Y143S [Y143A,G,H,S]) that emerge less frequently, and we compare the genotypic and phenotypic profiles of these viruses to Y143C,R viruses to reconcile the preferential selection of Y143C,R variants during RAL tre
HIV-1 integrase resistance among antiretroviral treatment naive and experienced patients from Northwestern Poland.
Introduction: Virologic failure has been associated with major, signature mutations within the catalytic domain of the enzyme, and include Y143R/C, N155H Q148K/R/H integrase sequence variants associated with significant susceptibility reduction both to RAL and elvitegravir (EVG) .
In-vivo selection of the mutation F121Y in a patient failing raltegravir containing salvage regimen.
Abstract: Different resistance mutations in HIV integrase from patients using these antiretroviral drugs have been described and G148H/R/K, N155H and less frequently Y143C/H/R are considered major resistant mutations to raltegravir.
Three main mutational pathways in HIV-2 lead to high-level raltegravir and elvitegravir resistance: implications for emerging HIV-2 treatment regimens.
Abstract: Collectively, our data define three major mutational pathways to high-level raltegravir and elvitegravir resistance: i) E92Q+Y143C or T97A+Y143C, ii) G140S+Q148R, and iii) E92Q+N155H.
Introduction: These additional changes cooperate with Y143C, Q148R and N155H to produce more substantial declines in drug susceptibility.
Introduction: We previously showed that the single amino acid changes Q148R and N155H in HIV-2 integrase confer moderate resistance to raltegravir, whereas the
"Prolonged and substantial discordance in prevalence of raltegravir-resistant HIV-1 in plasma versus PBMC samples revealed by 454 ""deep"" sequencing."
Introduction: Post-raltegravir-therapy evolution of raltegravir-associated DRMs in plasma samples is relatively well-characterized, with reports showing Q148H/K/R+G140S and N155H emerged before Y143R/H/C.
Introduction: Well-characterized mutations in the HIV-1 int region that confer high levels of resistance to raltegravir include E92Q, Y143R/H/C, Q148H/K/R and N155H.
Method: Out of the eight patients with DRMs, five of them developed at least one of the three major raltegravir resistance pathways (Y143R/C/H, Q148H/R/K and/or N15
Drug Susceptibility and Viral Fitness of HIV-1 with Integrase Strand Transfer Inhibitor Resistance Substitution Q148R or N155H in Combination with Nucleoside/Nucleotide Reverse Transcriptase Inhibitor Resistance Substitutions.
Abstract: CONCLUSION: This study confirms that HIV-2 resistance to RAL is due to the N155H, G140S/Q148R or E92Q/Y143C mutations.
Abstract: Recent studies have shown that HIV-2 resistance to raltegravir involves one of three resistance mutations, N155H, Q148R/H and Y143C, previously identified as resistance determinants in the HIV-1 integrase coding sequence.
Abstract: The <
Abstract: The genomes of the resistant strains were cloned and three patterns involving N155H, G140S/Q148R or Y143C mutations were identified.
HIV mutation literature information.
PMID: 
2014
The Journal of antimicrobial chemotherapy
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