Q148N, a Novel Integrase Inhibitor Resistance Mutation Associated with Low-Level Reduction in Elvitegravir Susceptibility.
PMID: 27009474
2016
AIDS research and human retroviruses
Discussion: Q148N is also the only mutation other than Q148H/R/K that has been shown to have strand transfer activity in biochemical assays.
Discussion: Of 1,120 integrase sequences from patients receiving raltegravir in GenBank as of June 2015, 23%, 8%, and 1% had the previously characterized INSTI-resistance mutations Q148H, Q148R, and Q148K, respectively.
Discussion: The rarity of Q148N and its weaker association with INSTI resistance suggest that it may be a revertant mutation arising from single nucleotide substitutions in viruses that once harbored Q148H (CAC or CAT) or Q148K
The design of 8-hydroxyquinoline tetracyclic lactams as HIV-1 integrase strand transfer inhibitors.
PMID: 27092410
2016
European journal of medicinal chemistry
Abstract: This manuscript describes a number of 8-hydroxyquinoline tetracyclic lactams with exceptional antiviral activity against HIV-1 and little loss of potency against the IN signature resistance mutations Q148K and G140S/Q148H.
Effect on HIV-1 viral replication capacity of DTG-resistance mutations in NRTI/NNRTI resistant viruses.
Discussion: Secondary integrase mutations(G140S/G and T97T/A) usually appeared together with Q148H/R and Y143Y/H.
Discussion: The ten major integrase mutations(including N155H, Y143C/R, Q148H/R, Y143Y/H, L74L/M, E92Q, E138E/A, Y143C, Q148Q and Y143S) could reduce the sensitivity of RAL and EVG.
Selectivity for strand-transfer over 3'-processing and susceptibility to clinical resistance of HIV-1 integrase inhibitors are driven by key enzyme-DNA interactions in the active site.
Abstract: However, these structures give only a partial sense for the limited inhibition of the 3'-processing reaction by INSTIs and how INSTIs can be modified to overcome drug resistance, notably against the G140S-Q148H double mutation.
Abstract: In addition, the G140S-Q148H (SH) mutant integrase, which has a reduced 3'-processing activity, becomes more active and more resistant to inhibition of 3'-processing by RAL and DTG in the absence of the -1 and +
Discussion: Here, we performed biochemical experiments and molecular modeling with the WT and the double-mutant (G140S-Q148H [SH]) that causes significant resistance to RAL and EVG and to a lesser extent to DTG.
Prevalence of Integrase Strand Transfer Inhibitors (INSTI) Resistance Mutations in Taiwan.
Abstract: Of 30 sequences (47.6%) with INSTI-resistant mutations from raltegravir-experienced patients, 17 harboured Q148H/K/R, 8 N155H, and 6 Y143C/R.
Abstract: Of these 12 sequences, 11 harboured Q148H/K/R, one Y143R, and none N155H.
Result: Among the INSTI-experienced patients, only one (1.6%) had Q148H/R/K along with two or three of G140A/C/S, L74I and E138A/K/T mutations and were predicted to have high-level resistance to dolutegravir.
Result: Among these sequences, Q148H/K/R
Drug resistant integrase mutants cause aberrant HIV integrations.
Abstract: More importantly, we show that at least two of the three clinically relevant drug resistant integrase mutants we te
Result: The G140S mutation is adjacent to Q148H.
Result: The Q148H mutation is also near the two metal ions at the IN active site, and the 3' end of the viral DNA.
Result: We tested three IN mutants, all of which reduced the susceptibility of the virus (and IN) to RAL, and caused a reduction in the relative infectivity of the single-round HIV vector used in our assay system (Y143R, residual titer is 40-45 % of WT; N155H, ~40 % of WT, and G140S/Q148H, 30-35 % of WT).
Development of a phenotypic susceptibility assay for HIV-1 integrase inhibitors.
PMID: 27737783
2016
Journal of virological methods
Abstract: Solely a Q148H+G140S variant presented reduced susceptibility to dolutegravir.
In vitro activity of dolutegravir against wild-type and integrase inhibitor-resistant HIV-2.
Result: Single amino acid changes T97A, G140S, Q148H and N155H had no significant effect on dolutegravir sensitivity (p > 0.05, ANOVA; Figure 2A).
Result: The ability of dolutegravir to inhibit strains resistant to other INSTI is of particular importance-in HIV-1, mutations Q148H/K/R, together with secondary changes in the integrase protein, confer resistance to dolutegravir in cell culture, and other mutations associated with diminished in vitro susceptibility to dolutegravir have been reported.
HIV mutation literature information.
PMID: 
2016
AIDS research and human retroviruses
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