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: Notably, the Y143R mutation had the most negative effect on RAL's antiviral activity consistent with the magnitude of the decrease in its dissociative t1/2, both of which were expected given the size, flexibility and formal charge of Arg.
Discussion: Note, from Table S1 in File S1, however, that EVG's dissociative t1/2 values with
Plasma raltegravir exposure influences the antiviral activity and selection of resistance mutations.
PMID: 21457126
2012
AIDS research and human retroviruses
Abstract: Integrase sequences could be obtained for 89 (84%), of whom 30 (33.7%) depicted primary RAL resistance mutations (15 N155H, eight Q148H/R, three Y143R, one E92Q, and three more than one of them).
Molecular dynamics approaches estimate the binding energy of HIV-1 integrase inhibitors and correlate with in vitro activity.
PMID: 22037850
2012
Antimicrobial agents and chemotherapy
Abstract: Four well-characterized compounds (raltegravir, elvitegravir, MK-0536, and dolutegravir) were used as a training set, and the data for their in vitro activity against the Y143R, N155H, and G140S/Q148H mutants were used in addition to the wild-type (WT) IN data.
PMID: 22107736
2012
Chemical biology & drug design
Abstract: A representative inhibitor (5e) retained most of its inhibitory potency against the three major raltegravir-resistant IN mutant enzymes, G140S/Q148H, Y143R, and N155H.
Abstract: In antiviral assays employing viral vectors coding these IN mutants, compound 5e was approximately 200- and 20-fold less affected than raltegravir against the G140S/Q148H and Y143R mutations, respectively.
Method: The following sense with cognate antisense (not shown) oligonucleotides (Integrated DNA Technologies, Coralville, IA) were used in the mutagenesis: Y143R, 5'-GCAGGAATTTGGCATTCCCCGCAATCCCCAAAGTCAAGGA-3'; N155H
Study of genotypic and phenotypic HIV-1 dynamics of integrase mutations during raltegravir treatment: a refined analysis by ultra-deep 454 pyrosequencing.
PMID: 22238474
2012
The Journal of infectious diseases
Abstract: At UDPS, not all resistant variants appearing early during treatment evolved as major populations during failure; only specific resistance pathways (Y143R-Q148H/R-N155H) associated with an increased rate of fitness and phenotypic resistance were selected.
Substitutions at amino acid positions 143, 148, and 155 of HIV-1 integrase define distinct genetic barriers to raltegravir resistance in vivo.
Abstract: Evaluation of molecular clones isolated from different time points demonstrated that Y143R and Q148H variants exhibited larger reductions in RAL susceptibility and higher IN-mediated replication capacity (RC) than N155H variants within the same subject.
Abstract: Furthermore, shifts from the N155H pathway to either the Q148R or H pathway or the Y143R pathway were dependent on the amino acid substitution at position 148 and the secondary mutations in Y143R- or Q148R- or H-containing variants and correlated with reductions in RAL susceptibility and restorations in RC.
Abstract: Patient viruses containing Y143R, PMID: 22564967
2012
Antiviral research
1Abstract: We report for the first time the ""in vivo"" selection F121Y and evolution to Y143R in a 31years old male clade B HIV-1 infected
Abstract: F121Y might be an alternative pathway to Y143R.
Abstract: At week 88 F121Y was no longer detected, L74I and T97A were maintained and Y143R emerged.
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.
The activity of the integrase inhibitor dolutegravir against HIV-1 variants isolated from raltegravir-treated adults.
PMID: 22878423
2012
Journal of acquired immune deficiency syndromes (1999)
Abstract: The median fold change to dolutegravir for isolates containing changes at G140S + Q148H, G140S + Q148R, T97A + Y143R, and N155H (thus including raltegravir signature resistance codons) were 3.75, 13.3, 1.05, and 1.37, respectively.
Three main mutational pathways in HIV-2 lead to high-level raltegravir and elvitegravir resistance: implications for emerging HIV-2 treatment regimens.
"Prolonged and substantial discordance in prevalence of raltegravir-resistant HIV-1 in plasma versus PBMC samples revealed by 454 ""deep"" sequencing."
Abstract: In the final paired samples that were tested while the subjects were on a raltegravir-containing regimen, DRM prevalence reached 100% in plasma but remained 1% in PBMC on day 177 post-therapy in Subject 3180 (Q148H/G140S), 100% in plasma and 36% in PBMC on day 224 in Subject 3242 (N155H), 78% in plasma and 11-12% in PBMC on day 338 in Subject 3501 (Q148H/G140S), and 100% in plasma and 0% in PBMC on day 197 in Subject 3508 (Y143R).
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
HIV mutation literature information.
PMID: 
2013
PloS one
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