Abstract: A major drug resistance mutation for raltegravir (RAL) and elvitegravir (EVG), Q148H, was retrieved from one patient and another RAL primary resistance mutation, Y143H, was also retrieved from another patient.
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
Dolutegravir interactions with HIV-1 integrase-DNA: structural rationale for drug resistance and dissociation kinetics.
Discussion: Although the Y143H mutation is not associated with a substantial loss in anti-HIV activity, the minor 1.8-fold increase in EC50 is likely associated with the decreased dissociative t1/2 of RAL.
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 Y143C/H/R mutations (Table S1 in File S1), respectively, provide evidence for the compromised inhibitor binding to the mutant enzymes.
Binding mode prediction of biologically active compounds from plant Salvia Miltiorrhiza as integrase inhibitor.
Discussion: The proposed raltegravir resistance pathway of the less frequently Y143H/R/C has been directly related to the interaction between inhibitor and Tyr143.
"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
Three main mutational pathways in HIV-2 lead to high-level raltegravir and elvitegravir resistance: implications for emerging HIV-2 treatment regimens.
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.
Switching between raltegravir resistance pathways analyzed by deep sequencing.
Introduction: Three codons can mutate to generate primary resistance mutations, which encode Y143R/C/H, Q148H/R/K, and N155H.
Result: A few substitutions show potential significance, including Y143H in all participants and Q148R in participant 3.
Result: Following correction for multiple comparisons, Y143H attained significance in both patient 1 and 3, but no other positions survived the test for multiple comparisons.
Result: However, after correction for multiple comparisons, only Y143H in participant 3 maintained significance.
Discussion: also investigated RAL resistance using 454 sequencing and reported detection of Y143H, Y143C
The HIV-1 integrase mutations Y143C/R are an alternative pathway for resistance to Raltegravir and impact the enzyme functions.
Abstract: The emergence of the N155H mutation was replaced by a pattern including the Y143R/C/H mutations in three patients with anti-HIV treatment failure.
Introduction: In a previous work, we reported how patients who had failed to respond to therapies under RAL-containing regimens presented the N155H mutation, which was then replaced over time by the Y143C/H/R mutations.
Introduction: The most frequent primary RAL resistance mutations emerging in vivo at virological failure (VF) in the IN gene are Q148H/R/K, N155H, and to a lesser extent Y143C/H/R.
Result: In all three patients, the initial selection of the N155H
A dynamic model of HIV integrase inhibition and drug resistance.
Discussion: In patients failing therapy with either raltegravir or elvitegravir, the mutations Y143R/C/H have been detected, but no mutations of H67 have been observed in patients.
HIV mutation literature information.
PMID: 
2013
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