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.
The G140S mutation in HIV integrases from raltegravir-resistant patients rescues catalytic defect due to the resistance Q148H mutation.
Discussion: It is important to note that the Q148H/R single mutation may occur 8 weeks after starting RAL treatment.
Discussion: Mutants Q148K/R displayed reduced viral fitness whatever the cell line studied (PBMC or Jurkat cells).
Discussion: The authors have studied the Q148K/R and G140S mutations as well as the G140S/
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.
Dynamic patterns of human immunodeficiency virus type 1 integrase gene evolution in patients failing raltegravir-based salvage therapies.
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-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.
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.
HIV mutation literature information.
PMID: 
2010
Biochemistry
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