Abstract: Mutations at positions involved in raltegravir resistance (E92G, G140S, Q148H, and N155H) were detected in 4 of 11 (36.3%) patients as early as 1 month after initiating salvage HAART.
Genotypic/phenotypic patterns of HIV-1 integrase resistance to raltegravir.
PMID: 20056687
2010
The Journal of antimicrobial chemotherapy
Abstract: DISCUSSION: Two patterns of viral evolution were observed in the resistant viral populations, driving the variants towards a fast (most of them with G140S + Q148H mutations) or progressive increase in resistance to raltegravir.
A dynamic model of HIV integrase inhibition and drug resistance.
Abstract: These models have allowed us to (1) explore the effects of key drug resistance mutations on the dynamic flexibility and conformational preferences of HIV integrase and to (2) study raltegravir binding in the context of these dynamic models of both wild type and the G140S/Q148H drug-resistant enzyme.
Method: During the first round of experiments with AutoDock4.0 that involved the four wild type targets and the ten targets of the G140S/Q148H mutant present in the QR2 subsets with a QH2 = 0.84, the charges on the magnesium ions and on the oxygen atoms of the DDE motif that coordinate them were derived from Quantum Mechanical simulations (QM) with Gaussian03.
Result: 4-5, our models predict a marked reduction in conformational flexibility for the G140S/
Biochemical and pharmacological analyses of HIV-1 integrase flexible loop mutants resistant to raltegravir.
Abstract: By examining systematically all of the double mutants at the 140 and 148 positions, we demonstrate that only the combination G140S + Q148H is able to restore the catalytic properties of IN.
Abstract: Clinical and virological data indicate the high relevance of the combination G140S + Q148H because of its limited impact on HIV replication and very high resistance to RAL.
Abstract: Finally, we show that the G140S-Q148H double mutant exhibits the highest resistance to RAL.
The HIV-1 integrase mutations Y143C/R are an alternative pathway for resistance to Raltegravir and impact the enzyme functions.
Introduction: Q148H is rescued by the G140S mutation.
Introduction: The Q148H mutation, which leads to a decreased activity of IN, confers a higher level of resistance to RAL than G140S or N155H.
Secondary integrase resistance mutations found in HIV-1 minority quasispecies in integrase therapy-naive patients have little or no effect on susceptibility to integrase inhibitors.
PMID: 20479206
2010
Antimicrobial agents and chemotherapy
Abstract: Secondary mutations, such as T97A and G140S, found rarely and only as minority quasispecies, were present in the elvitegravir-resistant clones.
Effect of raltegravir resistance mutations in HIV-1 integrase on viral fitness.
PMID: 20634701
2010
Journal of acquired immune deficiency syndromes (1999)
Abstract: Fitness was partially restored by the presence of additional RAL resistance mutations at positions G140S and E92Q or E138K, respectively.
Abstract: In the presence of RAL, the N155H mutant remained fitter than the Q148H mutant, but the G140S/Q148H double mutant was fitter than single mutants or the E92Q/N155H double mutant.
Abstract: The N155H mutants emerge first, and are eventually replaced by Q148H mutants, usually in combination with G140S.
Discussion: A third study found the G140A mutation in place of
Discovery of potent HIV integrase inhibitors active against raltegravir resistant viruses.
Abstract: Several compounds with excellent activities against wild-type virus as well as against the viruses with the mutations Q148H/G140S or N155H/E92Q were reported.
In-vitro phenotypic susceptibility of HIV-2 clinical isolates to the integrase inhibitor S/GSK1349572.
Abstract: We found a seven-, 13- and 18-fold increase in EC50 values to S/GSK1349572 for the HIV-2 double (T97A + Y143C; G140S + Q148R) and triple (G140T + Q148R + N155H) mutants, respectively, obtained from two raltegravir-experienced patients.
Molecular mechanisms of retroviral integrase inhibition and the evolution of viral resistance.
Abstract: Furthermore, our structures predict physical proximity and an interaction between HIV-1 IN mutant residues His148 and Ser/Ala140, rationalizing the coevolution of Q148H and G140S/A mutations in drug-resistant viral strains.
Abstract: We show that like the Q148H/G140S and N155H HIV-1 IN variants, the analogous S217H and N224H PFV INs display reduced sensitivity to raltegravir in vitro.
HIV mutation literature information.
PMID: 
2010
Journal of medical virology
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