Exploring the molecular mechanism of cross-resistance to HIV-1 integrase strand transfer inhibitors by molecular dynamics simulation and residue interaction network analysis.
PMID: 23231029
2013
Journal of chemical information and modeling
Abstract: On the basis of the homology modeling constructed structure of tetrameric HIV-1 intasome, the detailed molecular mechanism of the cross-resistance mutation E138K/Q148K to three important INSTIs (Raltegravir (RAL, FDA approved in 2007), Elvitegravir (EVG, FDA approved in 2012), and Dolutegravir (DTG, phase III clinical trials)) was investigated by using molecular dynamics (MD) simulation and residue interaction network (RIN) analysis.
Impact of primary elvitegravir resistance-associated mutations in HIV-1 integrase on drug susceptibility and viral replication fitness.
PMID: 23529738
2013
Antimicrobial agents and chemotherapy
Abstra
Abstract: Less commonly observed primary IN mutations also showed a range of reduced EVG susceptibilities: 40- to 94-fold for T66K and Q148K and 5- to 10-fold for T66A, E92G, and Q148H.
Abstract: Primary INSTI resistance-associated mutations (RAMs) at six IN positions have been identified in HIV-1-infected patients failing EVG-containing regimens in clinical studies: T66I/A/K, E92Q/G, T97A, S147G, Q148R/H/K, and N155H.
Binding mode prediction of biologically active compounds from plant Salvia Miltiorrhiza as integrase inhibitor.
Introduction: The secondary mutation at position G140 (G140S) combined with primary mutation Q148K/R/H significantly enhanced drug resistance.
Introduction: The two primary resistance pathways involved mutations of the amino acids at Q148 (Q148K/R/H) or N155 (N155/H) whereas a third primary mutation pathway at Y143 (Y143C/R) was less commonly found .
Dolutegravir interactions with HIV-1 integrase-DNA: structural rationale for drug resistance and dissociation kinetics.
Abstract: Signature HIV-1 integrase mutations associated with clinical raltegravir resistance involve 1 of 3 primary genetic pathways, Y143C/R, Q148H/K/R and N155H, the latter 2 of which confer cross-resistance to elvitegravir.
Introduction: In our efforts to structurally rationalize DTG's distinct resistance and dissociation kinetics profiles, we constructed wild-type, Q148R, Q148K, Q148H/G140S and N155H HIV-1 IN models in complex with U5 LTR DNA using carefully selected structural data from wild-type and mutant PFV intasomes as well as Tn5 transposase to model key missing active-site el
Three main mutational pathways in HIV-2 lead to high-level raltegravir and elvitegravir resistance: implications for emerging HIV-2 treatment regimens.
Result: Collectively, these data show that raltegravir-resistant mutants of HIV-2 are cross-resistant to elvitegravir and that substitutions T97A+143C, Q148K/R, G140S+Q148R and E92Q+N155H confer high-level elvitegravir resistance in HIV-2.
Result: In contrast, replacements Q148K and Q148R alone were sufficient for a >50-fold increase in the EC50 for elvitegravir (Figure 2C).
Result: More substantial changes were conferred by Q148K, Q148R, N155H and Table: Q148K/R
Table: Q148K
"Prolonged and substantial discordance in prevalence of raltegravir-resistant HIV-1 in plasma versus PBMC samples revealed by 454 ""deep"" sequencing."
Method: Out of the eight patients with DRMs, five of them developed at least one of the three major raltegravir resistance pathways (Y143R/C/H, Q148H/R/K and/or N155H/S), had longitudinal paired plasma and PBMC samples available, and had samples that could be successfully amplified and sequenced.
Method: Primary raltegravir-associated DRMs were defined to be E92Q, Y143R/C/H, Q148H/R/K, and N155H/S (HXB2 int amino acid coordinates), according to the International AIDS Society guidelines.
Method: Secondary raltegravir-associated DRMs were defined to be E92V, Q95K, PMID: 23259737
2012
BMC infectious diseases
Introduction: Virologic failure has been associated with major, signature mutations within the catalytic domain of the enzyme, and include Y143R/C, N155H Q148K/R/H integrase sequence variants associated with significant susceptibility reduction both to RAL and elvitegravir (EVG) .
Genetic variation of the HIV-1 integrase region in newly diagnosed anti-retroviral drug-naive patients with HIV/AIDS in Korea.
PMID: 20946407
2011
Clinical microbiology and infection
Abstract: Major mutation sites in the integrase (E92Q, F121Y, G140A/S, Y143C/R, Q148H/R/K and N155H) were not detected, and only a few minor mutation sites (L74M, V151I, E157Q, V165I, I203M, S230N and D232N) were identified in 21 strains (28%).
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.
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.
HIV mutation literature information.
PMID: 
2013
Journal of chemical information and modeling
Browser Board
Co-occurred Entities
Filtrator
ViMRT