Effect of raltegravir resistance mutations in HIV-1 integrase on viral fitness.
PMID: 20634701
2010
Journal of acquired immune deficiency syndromes (1999)
Introduction: Data from clinical trials show that RAL resistance involves IN mutations Y143C, Q148H or R or K or N155H, together with associated secondary mutations that result in higher levels of resistance.
Introduction: The N155H mutant generally emerges first, and is eventually replaced by Q148H mutants, usually in combination with G140S.
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,
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: 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 prolonged treatment.
Result: A similar pattern was observed with N155H and Q148H using RDS 1997 and RDS 2197 (data not shown).
Result: All three inhibitors were able to trap SC and H-SC formed with PMID: 21030679
2010
Proc Natl Acad Sci U S A
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.
Polymorphisms of HIV-2 integrase and selection of resistance to raltegravir.
Introduction: In HIV-1-infected patients failing an INI-containing regimen, three distinct resistance pathways involving Y143R, Q148H/R/K or N155 H have been described.
Introduction: The Q148 H mutation in combination with the G140 S secondary mutation confers the highest level of resistanc
Result: It is possible that the genetic context of the ROD strain, or its relative replicative capacity in the presence of RAL, might favor the emergence of strains harboring the Q91R+I175M mutations over other resistance pathways including the Q148 H/R/K and/or N155 H substitutions.
Extended use of raltegravir in the treatment of HIV-1 infection: optimizing therapy.
Abstract: The development of resistance to raltegravir mainly involved three resistance mutations in integrase gene: Q148H/K/R, N155H, and Y143C/H/R.
Discussion: Among raltegravir-resistant double mutants, the highest selective-advantage profile was seen with G140S + Q148H.
Discussion: Most of these shifts in raltegravir-resistance profiles were characterized by the loss of variants containing N155H and the emergence of variants containing Q148R/H or, in a few cases, Y143C/R.
Discussion: Of the 11 assessable patients who displayed a viral rebound on raltegravir-based therapy, virus with mutations known to confer raltegravir
The G140S mutation in HIV integrases from raltegravir-resistant patients rescues catalytic defect due to the resistance Q148H mutation.
Introduction: (ii) In most cases, the Q148H mutation occurs simultaneously with the G140S mutation.
Introduction: Accordingly, the in vitro activity of the G140S/Q148H mutant can reach a wild-type level of activity while the single mutant Q148H cannot.
Introduction: Finally, we found that the G140S/Q148H mutant was much more resistant than the N155H mutant.
Introduction: In particular, we investigated the effect of the G140S/Q148H double mutation, by constructing both the Q148H and G140S single mutants as well as the double mutant.
HIV-1 integrase polymorphisms are associated with prior antiretroviral drug exposure.
Introduction: These occur in one of two main pathways, either N155H or Q148H/K/R.
Introduction: This mutation is not only responsible for partial RAL resistance but also restores viral fitness when combined with the Q148R/H mutation.
Introduction: in their review of the Stanford HIV Database in only 3 isolates (each with a single primary INI mutation N155H, Q148H and Q148K).
Quasispecies variant dynamics during emergence of resistance to raltegravir in HIV-1-infected patients.
PMID: 19221102
2009
The Journal of antimicrobial chemotherapy
Abstract: In most patients, raltegravir failure is associated with mutations in the IN gene, through two different genetic pathways: 155 (N155H) or 148 (Q148K/R/H).
Abstract: In the two patients switching from the 155 to the 148 pathway, clonal analysis showed that Q148R/H and N155H mutations were present on different strands, suggesting that these two pathways are independent.
Abstract: We observed a greater variability among quasispecies associated with the 155 pathway, and IC(50) determinations showed that the fold resistance to raltegravir, relative to wild-type, was 10 for the N155H mutant and 50 for the G140S+Q148H mutant.
Lack of primary mutations associated with integrase inhibitors among HIV-1 subtypes B, C, and F circulating in Brazil.
PMID: 19262402
2009
Journal of acquired immune deficiency syndromes (1999)
Abstract: Major mutations associated with elvitegravir or raltegravir in vivo resistance (Q148K/H/R, N155H) were not detected.
HIV mutation literature information.
PMID: 
2010
Journal of acquired immune deficiency syndromes (1999)
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