Cross-resistance profile determination of two second-generation HIV-1 integrase inhibitors using a panel of recombinant viruses derived from raltegravir-treated clinical isolates.
PMID: 20956600
2011
Antimicrobial agents and chemotherapy
Abstract: Samples with Q148H/R mutations had elevated fold change values with all compounds tested.
HIV-1 integrase strand transfer inhibitors stabilize an integrase-single blunt-ended DNA complex.
Result: RAL resistance primarily occurs through several independent pathways containing mutations in IN (N155H and Q148H/K/R), with secondary mutations generally producing larger reductions in RAL susceptibility.
Subtype diversity associated with the development of HIV-1 resistance to integrase inhibitors.
Abstract: Thirteen patients failed raltegravir (RAL)-containing regimens within 8 +- 1 months, in association with the major Q148K/R/H and G140A/S (n = 8/24) or N155H (n = 5/24) mutational pathways.
Resistance associated mutations to dolutegravir (S/GSK1349572) in HIV-infected patients--impact of HIV subtypes and prior raltegravir experience.
Abstract: E92Q and Q148H/R were only seen in raltegravir-experienced patients and exclusively infected with subtype B (1.9% vs. 0%, p=0.026, for E92Q and 12.6% vs. 0%, p<0.001, for Q148H/R).
Abstract: T124A was more frequent in INI-naive patients but E92Q and Q148H/R were only seen in raltegravir-experienced individuals.
Single mutations in HIV integrase confer high-level resistance to raltegravir in primary human macrophages.
PMID: 21628534
2011
Antimicrobial agents and chemotherapy
Abstract: We show here that during macrophage infection, the presence of a single primary raltegravir resistance mutation (Q148H, Q148R, N155H, or N155S) is sufficient to provide resistance to raltegravir comparable to that seen in viruses expressing both primary and secondary mutations in costimulated CD4(+) T cells.
Resistance to raltegravir highlights integrase mutations at codon 148 in conferring cross-resistance to a second-generation HIV-1 integrase inhibitor.
Abstract: This was confirmed by phenotypic analysis of 766 clonal viruses harboring IN sequences isolated at the point of virological failure from 106 patients on HAART (including RAL), where mutation Q148H/K/R together with additional secondary mutations conferred reduced susceptibility to both RAL and MK-2048.
Switching between raltegravir resistance pathways analyzed by deep sequencing.
Result: A few substitutions show potential significance, including Y143H in all participants and Q148R in participant 3.
Discussion: Our findings taken together support the idea that Y143H, and possibly Y143C and Q148R, are authentic replication-competent polymorphisms that are present in viral populations in the absence of RAL.
Discussion: The Y143C and Q148R substitutions were marginally significant by some measures but did not survive correction for multiple comparisons.
Discussion: also investigated RAL resistance using 454 sequencing and reported detection of Y143H, Y143C, and Q148R prior to initiation of therapy.
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.
Introduction: By comparing these isolates with IN mutants generated by single-site mutagenesis, we demonstrate that G140S/Q148R and N155H are sufficient to confer resistance to RAL, whereas Y143C mutation is not.
Introduction: The virological failure of RAL-based treatment in HIV-1 infection is associated primarily with the initial, independent development of the principal N155H and Q148H/K/R pathways, either alone or together with other resistance mutations.
Method: Single (E92Q, T97A, G140S, Q148R, Y143C, N155H) and
Long-lasting persistence of integrase resistance mutations in HIV-2-infected patients after raltegravir withdrawal.
Abstract: In patient 1, the G140S/Q148R double-mutant was still detected at month (M)7 and at M11 after stopping RAL, but was no longer detected at M15.
Abstract: RESULTS: At the time of RAL withdrawal, virus exhibited different integrase resistance pathways: G140S/Q148R, E92Q/N155H, T97A/N155H and T97A/Y143C.
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: Amino acid changes Q148R and N155H individually conferred resistance to raltegravir (14-fold and seven-fold, respectively), whereas the Y143C replacement had no statistically significant effect on raltegravir sensitivity.
Abstract: CONCLUSION: Our data support clinical studies of raltegravir for treating HIV-2 infection and show that the Q148R and N155H changes alone are sufficient for raltegravir resistance in HIV-2.
Abstract: The combination of Q148R with N155H resulted in high-level raltegravir resistance (>1000-fold).
Discussion: 2) and that the Q148R and N155H changes individually confer moderate r
HIV mutation literature information.
PMID: 
2011
Antimicrobial agents and chemotherapy
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