Progressive emergence of an S153F plus R263K combination of integrase mutations in the proviral DNA of one individual successfully treated with dolutegravir.
Abstract: CONCLUSION: The DTG-resistant R263K substitution antagonized the development of HIV-1 resistance against RAL while partially facilitating the occurrence of resistance against EVG.
Abstract: DESIGN AND METHODS: We performed tissue culture selection experiments using DTG-resistant viruses containing integrase substitutions at positions R263K, H51Y/R263K, E138K/R263K, G118R and H51Y/G118R in the presence of increasing concentrations of either RAL or EVG.
Abstract: In contrast, resistance against EVG appeared earlier than in wild-type virus in viruses containing the R263K and
Characterization of the Drug Resistance Profiles of Integrase Strand Transfer Inhibitors in Simian Immunodeficiency Virus SIVmac239.
Abstract: To study this at a biochemical level, purified recombinant SIVmac239 wild-type (WT) and E92Q, T97A, G118R, Y143R, Q148R, N155H, R263K, E92Q T97A, E92Q Y143R, R263K H51Y, and G140S Q148R recombinant substitution-containing IN enzymes were produced, and each of the characteristics strand transfer, 3'-processing activity, and INSTI inhibitory constants was assessed in cell-free as
Lack of integrase inhibitors associated resistance mutations among HIV-1C isolates.
PMID: 26626277
2015
Journal of translational medicine
Discussion: This includes T66IAK, E92Q, F121Y, G140SA, Y143HCR, Q146P, S147G, Q148KHR, and N155HS; (2) minor INI-resistance mutations were defined as non-polymorphic or minimally polymorphic mutations that reduce INI susceptibility H51Y, L74 M, T97A, E138AK, S153Y,
Resistance against Integrase Strand Transfer Inhibitors and Relevance to HIV Persistence.
Abstract: We review here the issue of drug resistance against integrase strand transfer inhibitors as well as both pre-clinical and clinical studies that have led to the identification of the R263K mutation in integrase as a signature resistance substitution for dolutegravir.
Introduction: Although substitutions at positions M50I, H51Y or E138K emerged under DTG pressure after R263K, none of these was able to restore viral replicative capacity to wild-type levels.
Introduction: Furthermore, there is a high degree of likelihood that DTG will remain active against the latter viruses because of the very long dissociative half-life between DTG and integrase protein, very tight binding between DTG and
Resistance mutations against dolutegravir in HIV integrase impair the emergence of resistance against reverse transcriptase inhibitors.
Abstract: DESIGN AND METHODS: We tested the ability of DTG-resistant viruses containing either the R263K or G118R and/or H51Y mutations to develop further resistance against several reverse transcriptase inhibitors during in-vitro selection experiments.
Abstract: Now, we sought to investigate the facility with which resistance on the part of R263K-containing viruses might develop.
Abstract: The R263K integrase resistance mutation was observed in two of these individuals who received suboptimal background regimens.
Abstract: We have previously selected mutations at position R263K, G118R, H51Y, and S153F plus R263K combination of integrase mutations in the proviral DNA of one individual successfully treated with dolutegravir.
Introduction: As such, tissue culture selection studies with this drug have revealed the emergence of the R263K mutation in the integrase of HIV subtypes B and circulating recombinant form CRF02_A/G viruses .
Introduction: Here, we present the biochemical characterization of the M50I substitution alone and in combination with the primary resistance mutation R263K in subtype B integrase.
Introduction: However, the R263K mutation has been found in INSTI-naive ART-experienced patients receiving DTG treatment who have failed therapy with this drug .
Introduction: In addition, this polymorphism has been observed in combination with R263K in a patient who subsequently failed treatment with RAL .|mgd
HIV-2 integrase polymorphisms and longitudinal genotypic analysis of HIV-2 infected patients failing a raltegravir-containing regimen.
Introduction: Corroborating this is the fact that, at this time, it is still unknown whether the combination H51Y/R263K, that confers some level of resistance to DTG in HIV-1, could be relevant as a mutational pathway leading to HIV-2 resistance.
Progressive emergence of an S153F plus R263K combination of integrase mutations in the proviral DNA of one individual successfully treated with dolutegravir.
PMID: 24917583
2014
The Journal of antimicrobial chemotherapy
Abstract: CONCLUSIONS: The E138K substitution failed to restore the defect in viral replication capacity that is associated with R263K, confirming previous selection studies that failed to identify compensatory mutation(s) for the latter primary mutation.
Abstract: METHODS: We used biochemical cell-free strand-transfer assays and tissue culture assays to characterize the effects of the E138K/R263K combination of mutations on resistance to dolutegravir, integrase enzyme activity and HIV-1 replication capacity.
Abstract: RESULTS: We show here that the addition of the E138K substitution to R263K increased the resistance of HIV-1 to dolutegravir but failed to restore viral replication capacity, integrase str
Fitness impaired drug resistant HIV-1 is not compromised in cell-to-cell transmission or establishment of and reactivation from latency.
Abstract: Here, we have studied the impact of R263K on HIV replication capacity and the ability of HIV to establish or be reactivated from latency and/or spread through cell-to-cell transmission.
Abstract: The clinical use of a novel integrase inhibitor, dolutegravir (DTG), has established hope that this compound may limit HIV persistence, since no treatment-naive patient treated with DTG has yet developed resistance against this drug, even though a R263K substitution in integrase confers low-level resistance to this drug in tissue culture.
Introduction: Altogether, these observations suggest that R263K may represent an evolutionary dead-end that could explain the scarcity of virological failures and resistance mutations in individuals treated with DTG.
Introduction: Further studies have shown that se
Progressive emergence of an S153F plus R263K combination of integrase mutations in the proviral DNA of one individual successfully treated with dolutegravir.
PMID: 25394027
2014
Journal of the International AIDS Society
Abstract: CONCLUSIONS: Secondary mutations to R263K following selection with DTG have all led to diminished viral and enzymatic fitness, helping to explain why resistance to DTG in previously drug-naive subjects has never been observed.
Abstract: Conversely, combinations of R263K together with multiple resistance mutations for RAL and/or EVG at positions 92,143, 148 and 155 resulted in even further diminished enzymatic activity that may be incompatible with viral survival.
Abstract: In contrast, a R263K mutation that confers low-level resistance (3-4 fold) to DTG has been selected by DTG in culture.
Abstract: Modelling of the 3-dimensional structure of integrase suggests that R263K is located in a region that may not permit further mutagenesis if secondary mutations at H51Y
HIV mutation literature information.
PMID: 
2015
AIDS (London, England)
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