Abstract: OBJECTIVE: : Resistance to raltegravir is associated with three genetic pathways defined by the mutations Y143R/C, Q148H/R/K or N155H in integrase, which also infer a viral fitness cost.
Impact of Y143 HIV-1 integrase mutations on resistance to raltegravir in vitro and in vivo.
PMID: 19901095
2010
Antimicrobial agents and chemotherapy
Abstract: A molecular modeling study confirmed that Y143R/C mutations play a role similar to that determined for Q148R/H mutations.
Abstract: Furthermore, the 50% effective concentration (EC(50)) determined for Y143R/C mutants was significantly higher than that obtained with G140S/Q148R mutants.
Abstract: However, Y143R/C activity can be kinetically restored, thereby reproducing the effect of the secondary G140S mutation that rescues the defect associated with the Q148R/H mutants.
A dynamic model of HIV integrase inhibition and drug resistance.
Result: During clinical studies of raltegravir, three pathways to resistance have been observed involving residues N155H, Q148H/K/R, and Y143C/R.
Drug Susceptibility and Viral Fitness of HIV-1 with Integrase Strand Transfer Inhibitor Resistance Substitution Q148R or N155H in Combination with Nucleoside/Nucleotide Reverse Transcriptase Inhibitor Resistance Substitutions.
Abstract: Allele-specific real-time PCR (AS-PCR) systems, developed for Q148H, Q148R and N155H mutations, were performed at baseline for antiretroviral-experienced patients.
Abstract: CONCLUSION: Q148R variants were frequently detected, always at low-level, in antiretroviral-experienced and naive patients.
Abstract: However, we did not find any association between the presence of Q148R minority variants and an increased risk of virological failure.
Abstract: In antiretroviral-experienced patients, Q148R minority variants were frequently detected (26/32 patients, 81%) at low-level frequency (median = 0.40%), whereas no minority variants exhibiting Q148H or N155H mutation were found.
Biochemical and pharmacological analyses of HIV-1 integrase flexible loop mutants resistant to raltegravir.
Abstract: Resistance to raltegravir (RAL), the first HIV-1 integrase (IN) inhibitor approved by the FDA, involves three genetic pathways: IN mutations N155H, Q148H/R/K, and Y143H/R/C.
Natural polymorphisms of integrase among HIV type 1-infected South African patients.
PMID: 20377427
2010
AIDS research and human retroviruses
Abstract: Amino acid sequence analysis revealed there were no primary mutations (Y143R/C/H, Q148H/R/K, and N155H/S) associated with reduced susceptibility to the integrase inhibitors raltegravir and elvitegravir.
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.
Abstract: The median raltegravir and elvitegravir fold changes (FCs) were 244 (154-647) and 793 (339-892), respectively,
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.
Introduction: The most frequent primary RAL resistance mutations emerging in vivo at virological failure (VF) in the IN gene are Q148H/R/K, N155H, and to a lesser extent Y143C/H/R.
Method: We followed-up the 50 mutations of resistance present at 32 positions: associated with in vitro or in vivo resistance to HIV-1 integrase inhibitors: H51Y, T66I/A/K, V72I, L74I/A/M, E92Q, T97A, T112I, F121Y, T125K, A128T,
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.
HIV mutation literature information.
PMID: 
2010
AIDS (London, England)
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