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).
Subtype diversity associated with the development of HIV-1 resistance to integrase inhibitors.
Abstract: These variations predicted higher genetic barriers to G140S and G140C in subtypes C, CRF02_AG, and A/CRF01_AE, as well as higher genetic barriers toward acquisition of V151I in subtypes CRF02_AG and A/CRF01_AE.
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.
Transmission of integrase strand-transfer inhibitor multidrug-resistant HIV-1: case report and response to raltegravir-containing antiretroviral therapy.
Abstract: The virus harboured INI drug resistance substitutions (Q148H and G140S) along with multiple reverse transcriptase and protease inhibitor resistance mutations.
Switching between raltegravir resistance pathways analyzed by deep sequencing.
Abstract: RESULTS: All three patients showed transitions from the N155H pathway to the Q148H/G140S pathway.
Result: A different lineage derived from the same ancestral group emerged at month 5 and acquired the Q148H + G140S mutations, which persisted there-after.
Result: Each of the collections of DRMs (N155H, Q148R, and Q148H + G140S) was found on both backgrounds.
Result: However, for the G140S mutation, the codon is directly adjacent to the polymorphic codon 139, so in this case, recombination would need to break exactly between the two codons to generate the observed genotypes.
Result: Patient 2 also showed
G140S/Q148R and N155H mutations render HIV-2 Integrase resistant to raltegravir whereas Y143C does not.
Method: Single (E92Q, T97A, G140S, Q148R, Y143C, N155H) and double (G140S/Q148R, Y143C/N155H, E92Q/Y143C and T97A/Y143C) mutations were introduced into the HIV-2 wild-type N1 sequence by mutagenesis using the QuickChange II site-directed mutagenesis kit (Agilent Technologies, Santa Clara, USA) according to the manufacturer instructions.
Result: All group A viruses harbored a Q148R resistance mutation, associated with G140S in two case
MK-0536 inhibits HIV-1 integrases resistant to raltegravir.
PMID: 21876054
2011
Antimicrobial agents and chemotherapy
Abstract: It is also effective against INs that carry the three main RAL resistance mutations (Y143R, N155H, and to a lesser extent G140S-Q148H) and against the G118R mutant.
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.
Phenotypic susceptibility of HIV-2 to raltegravir: integrase mutations Q148R and N155H confer raltegravir resistance.
Discussion: Studies of HIV-1 patients have identified three principal mutational patterns that emerge in response to raltegravir treatment: Q148H/K/R with or without G140S/A, N155H with or without E92Q and Y143C/R with or without T97A.
Discussion: recently showed that the combination of G140S with Q148R confers a more than 100-fold loss of raltegravir sensitivity in cell-free assays with purified integrase proteins.
The HIV-1 integrase genotype strongly predicts raltegravir susceptibility but not viral fitness of primary virus isolates.
Abstract: The first had the mutations G140S+Q148H+S230N, the second had Y143R+G163R and the third had no evidence of genotypic resistance in integrase.
Impact of Y143 HIV-1 integrase mutations on resistance to raltegravir in vitro and in vivo.
PMID: 19901095
2010
Antimicrobial agents and chemotherapy
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.
HIV mutation literature information.
PMID: 
2011
Antimicrobial agents and chemotherapy
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