Effect of raltegravir resistance mutations in HIV-1 integrase on viral fitness.
PMID: 20634701
2010
Journal of acquired immune deficiency syndromes (1999)
Result: The Q148R and Q148K mutants were fitter than the Discussion: Clones with G140S/Q148H showed higher integrase-mediated replication capacity as compared to clones with Q148R or N155H alone; the G140S/Q148H clones also exhibited higher levels of raltegravir resistance.
Discussion: In that study, the appearance of viruses with the Q148R or N155H mutations initially was associated with reduced replication capacity, but replication capacity returned towards wild-type levels as Q148H and G140S mutations emerged.
Physical trapping of HIV-1 synaptic complex by different structural classes of integrase strand transfer inhibitors.
Introduction: In most patients, mutations in IN responsible for RAL failure are represented in two independent genetic pathways; N155H and Q148H/R/K accounting for a severe loss (10-25 fold) in susceptibility to RAL with additional secondary mutations.
Introduction: In the patients enrolled for elvitegravir (EVG) studies, T66I, E92Q, Q148R and N155H mutations are primary contributors to EVG resistance.
Discussi
Discussion: An in-silico study of N155H and Q148H/R/K demonstrated that the structure of flexible loop (residues 140-148) in catalytic domain is conserved suggesting IN would be catalytically active.
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: 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.
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: RAL resistance is not well documented for HIV-2, although cases of therapy failure have been associated with the emergence of variants carrying the Y14
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: 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 resistance was found in eight patients: N155H (n = 6); Q148H/K/R +- G140S (n = 2);
Secondary mutations in viruses resistant to HIV-1 integrase inhibitors that restore viral infectivity and replication kinetics.
Abstract: Integrase-resistant mutations Q148K and Q148R were identified as primary mutations with the passage of HIV-1 IIIB in the presence of INIs S-1360 or S/GSK-364735, respectively.
Abstract: In contrast, Q148K/G140S and Q148R/E138K had nearly equivalent or slightly reduced fold resistance to the INI compared with their respective Q148 primary mutants, and had increases in infectivity and replication kinetics.
G140S/Q148R and N155H mutations render HIV-2 Integrase resistant to raltegravir whereas Y143C does not.
Discussion: The authors have studied the Q148K/R and G140S mutations as well as the G140S/Q148R and G140S/Q148K double mutants.
Discussion: and our study show that the G140S mutation rescues the ability of the Q148H/K/R mutants to replicate in cells while mutation of the Q148 residue is responsible for the resistance to the drug.
Discussion: have shown that the G140S mutation rescues the fitness of the Q148K/R mutant.
The G140S mutation in HIV integrases from raltegravir-resistant patients rescues catalytic defect due to the resistance Q148H mutation.
Abstract: RESULTS: : Resistance to RAL appeared initially associated with selection of single variants (Y143R, Q148R N155H) in the majority of patients; however, in three patients, complex patterns of viral mutations were observed.
HIV mutation literature information.
PMID: 
2010
Journal of acquired immune deficiency syndromes (1999)
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