HIV-1 resistance patterns to integrase inhibitors in antiretroviral-experienced patients with virological failure on raltegravir-containing regimens.
PMID: 20388636
2010
The Journal of antimicrobial chemotherapy
Abstract: Four different patterns of IN mutations were observed: (i) emergence of Q148H/R with secondary mutations (n=5 patients); (ii) emergence of N155H, then replaced by a pattern including Y143C/H/R (n=3); (iii) selection of S230N (n=1); and (iv) no evidence of selection of IN mutations (n=2).
Abstract: The median plasma raltegravir Cmin was lower in patients with selection of the N155H mutation followed by Y143C/H/R compared with patients with Q148H/R and with patients without emerging mutations or without VF.
Primary mutations selected in vitro with raltegravir confer large fold changes in susceptibility to first-generation integrase inhibitors, but minor fold changes to inhibitors with second-generation resistance profiles.
Abstract: Characterization of the phenotypic evolution showed that the switch from N155H to Y143C/R was linked to an increase in resistance to RAL.
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.
Table: N155N/H
Dis
Discussion: In all the patients, Y143R/C with secondary mutations replaced the N155H mutation.
Discussion: Interestingly, in all three patients, the N155H mutation appeared at M1 or M3, and then disappeared with a switch to the emergence of the Y143C/H/R mutation detected 3 months later.
Effect of raltegravir resistance mutations in HIV-1 integrase on viral fitness.
PMID: 20634701
2010
Journal of acquired immune deficiency syndromes (1999)
Result: By contrast, introduction of L74M into a N155H backbone further reduced viral fitness in the absence of drug, but resulted in increased fitness in the presence of drug.
Result: By contrast, the E92Q/N155H mutant was fitter than the E138K/Q148H mutant both in the absence and presence of 5.0 microM RAL (Table 2).
Result: Compared to WT, the N155H mutation conferred 19-fold resistance, and the Q148H(R) (K) mutations conferred 7- to 22-fold resistance to raltegravir.
Result: Fitness of N155H mutants.
Result: In the absence of drug, the relative fitness difference for WT versus N155H was 3.4-fold, whereas in the pr
HIV-1 subtype B and C integrase enzymes exhibit differential patterns of resistance to integrase inhibitors in biochemical assays.
Abstract: CONCLUSION: Polymorphic differences within the subtype B and C integrase genes likely cause variations in the contribution of N155H alone or in combination with E92Q to drug resistance.
Abstract: METHODS: We compared the susceptibility of subtype B and C HIV-1 integrase enzymes, harboring the previously reported resistance mutations E92Q, N155H, and E92Q/N155H, to clinically relevant integrase inhibitors.
Abstract: RESULTS: Subtype C integrase enzymes bearing the resistance mutations E92Q/N155H were approximately 10-fold more susceptible to each of two
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.
Physical trapping of HIV-1 synaptic complex by different structural classes of integrase strand transfer inhibitors.
Abstract: Notably, MK-2048 is equally potent against wild-type IN and raltegravir-resistant IN mutant N155H, suggesting this inhibitor may bind similarly within their drug-binding pockets.
Abstract: Studies of raltegravir-resistant IN mutants N155H and Q148H without inhibitors demonstrated that their capacity to assemble the synaptic complex and promote concerted integration was similar to their reported virus replication capacities.
Abstract: The concerted integration activity of Q148H showed a higher cross-resistance to raltegravir than observed with N155H, providing evidence as to why the Q148H pathway with secondary mutations is the predominant pathway upon prolong
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.
Dynamic escape of pre-existing raltegravir-resistant HIV-1 from raltegravir selection pressure.
Abstract: Double 148R+N155H mutants were also detected in 1.7% of viruses at virological failure in association with E138K and/or G163R.
Abstract: Using quantitative deep HIV-1 sequencing in a subject who developed virological failure to deep salvage therapy with raltegravir, we found that most Q148R and N155H mutants detected at the time of virological failure originated from pre-existing minority Q148R and N155H variants through independent evolutionary clusters.
Molecular mechanisms of retroviral integrase inhibition and the evolution of viral resistance.
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
The Journal of antimicrobial chemotherapy
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