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 the N155H mutation had no reduced susceptibility to compound G.
In Vitro antiretroviral properties of S/GSK1349572, a next-generation HIV integrase inhibitor.
PMID: 21115794
2011
Antimicrobial agents and chemotherapy
Abstract: S/GSK1349572 demonstrated activity against site-directed molecular clones containing the raltegravir-resistant signature mutations Y143R, Q148K, N155H, and G140S/Q148H (FCs, 1.4, 1.1, 1.2, and 2.6, respectively), while these mutants led to a high FC in the EC(50) of raltegravir (11- to >130-fold).
HIV-1 integrase strand transfer inhibitors stabilize an integrase-single blunt-ended DNA complex.
Abstract: In contrast, MK-2048 and L-841,411 produced ~3-fold to 5-fold more ISD than RAL with N155H IN, which is susceptible to these two inhibitors.
Abstract: The RAL-resistant IN mutant N155H weakly forms the ISD complex in the presence of RAL at ~25% level of wild-type IN.
Result: A similar reduction in the formation of the ISD complex with RAL was obtained if wt IN and N155H IN were used from the HIV IIIB strain (data not shown) In summary, the results suggest that IN possessing the N155H mutation lacks the capacity to efficiently form the ISD complex in the presence of RAL but efficiently forms the ISD with MK-2048 an
Emerging integrase inhibitor resistance mutations in raltegravir-treated HIV-1-infected patients with low-level viremia.
Abstract: Among them, three [7.7%, 95% confidence interval (CI) 1.6-20.9%] had significant INSTI resistance mutations consisting of N155H in two and P145S in one.
Result: Among the patients with a genotype result, three [7.7%, 95% confidence interval (CI) 1.6-20.9%] had INSTI resistance associated mutations consisting of N155H in two and P145S in one; all three were enrolled in the switch arm.
Result: Plasma HIV-1 RNA levels for the two patients with N155H mutant virus remained below 200 copies/ml at months 34 and 17, respectively, on continued raltegravir treatment.
Result: The N155H mutation was not detected in proviral DNA from PBMC obtained at entry from either patient.
Discussion
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.
Drug resistance mutations in patients infected with HIV-2 living in Spain.
PMID: 21558334
2011
The Journal of antimicrobial chemotherapy
Abstract: Two of the three patients who failed on raltegravir had N155H in the INT region.
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: N155H, a RAL-associated primary resistance mutation, was selected after IVRS with MK-2048, suggesting similar mechanisms of resistance to RAL and MK-2048.
Switching between raltegravir resistance pathways analyzed by deep sequencing.
Introduction: Here we investigated three patients for whom conventional viral population genotyping identified an N155H to Q148H pathway switch.
Introduction: Specifically, the N155H pathw
Discussion: One of the main questions in initiating this analysis was whether the first resistance mutation to arise, N155H, was present prior to initiating therapy.
Discussion: This is consistent with the idea that viruses with N155H or Q148H substitutions are considerably less fit than wild-type and so are very low in abundance in the absence of pressure from RAL.
Discussion: We analyzed the evolutionary dynamics of RAL DRMs for three patients who showed a switch from the N155H to the Q148H pathway.
G140S/Q148R and N155H mutations render HIV-2 Integrase resistant to raltegravir whereas Y143C does not.
Result: Biochemical studies have demonstrated that Q148R, N155H and Y143C are primary resistance mutations giving rise to HIV-1 resistance whereas G140S/A and E92Q are secondary resistance mutations increasing resistance and viral fitness.
Result: By contrast, the N155H mutation had no significant effect on IN activity.
Result: Consistent with this hypothesis, the catalytic activity of the Y143C/N155H recombinant mutant was strongly increased by the addition of 10% DMSO (data not shown), probably because DMSO may help to stabilize partially folded conformations of proteins.
HIV mutation literature information.
PMID: 
2011
Antimicrobial agents and chemotherapy
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