Abstract: Although no detectable differences in the levels of cell-free acetylation of the wild-type (WT) and mutated R263K enzymes were observed, the inhibition of cellular histone acetyltransferase enzymes sensitized the NL4.3WT virus to DTG, while NL4.3R263K was almost completely unaffected.
Abstract: Here we report that regulation of the acetylation of integrase is integral to the replication of HIV in the presence of DTG and that the R263K mutation specifically disrupts this regulation, likely due to enhancement of interactions with the histone deacetylase I complex, as suggested by coimmunoprecipitation assays.
Abstract: However, resistance against the newest integrase inhibitor, dolutegravir (DTG), is associated with an R263K substitution at the C terminus of
HIV-1 strains belonging to large phylogenetic clusters show accelerated escape from integrase inhibitors in cell culture compared with viral isolates from singleton/small clusters.
PMID: 28472323
2017
The Journal of antimicrobial chemotherapy
Abstract: With dolutegravir, large cluster HIV-1 variants acquired solitary R263K ( n= 7), S153Y ( n= 1) or H51Y ( n= 1) mutations as the dominant quasi-species within 8-12 weeks as compared with small cluster lineages where R263K ( n= 1/6), S153Y (1/6) or WT species (4/6) were observed after 24 weeks.|m
Introduction: Dolutegravir is far less prone to the development of resistance in first-line therapy with isolated reported cases of the emergence of R263K, N155H or G118R.
Introduction: However, the rapid acquisition of R263K or S153Y mutations with dolutegravir compromised viral replicative competence and hindered viral breakthrough.
Progressive emergence of an S153F plus R263K combination of integrase mutations in the proviral DNA of one individual successfully treated with dolutegravir.
Result: H51Y is a substitution that can be selected under DTG pressure secondary to R263K and that further decreases integration compared to the latter mutation.
Result: Given that integration is diminished by the R263K substitution in short-term infections, we investigated the effect of prolonged infections on the levels of integrated DNA.
Result: In order to exclude an effect of the R263K substitution on reverse transcription, we performed infections in Jurkat cells with the wild-type (WT) and R263K NL4-3 viruses and measured early and late reverse transcripts at various times after infection.
Result: Measuring the RT activity in the cell-free culture fluids showed similar decreases in the production of infectious viral particles
Effect on HIV-1 viral replication capacity of DTG-resistance mutations in NRTI/NNRTI resistant viruses.
Abstract: H51Y/R263K plus a RT mutation, and moderately reduced in double mutants.
Abstract: Although rare, emerging resistance against DTG is often associated with the R263K substitution in integrase.
Abstract: Given the reduced fitness of RTI-resistant viruses, we investigated potential impacts on viral replication of combining R263K and H51Y/R263K with major RTI-resistance substitutions including K65R, L74V, K103N, E138K, and M184I/V.
Progressive emergence of an S153F plus R263K combination of integrase mutations in the proviral DNA of one individual successfully treated with dolutegravir.
PMID: 27084918
2016
The Journal of antimicrobial chemotherapy
Abstract: Although R263K is the most common resistance substitution for the INSTI dolutegravir, an INSTI treatment-experienced individual recently failed dolutegravir-based therapy, with E157Q being the only resistance-associated change reported.
Abstract: CONCLUSIONS: This study shows that E157Q may act as a compensatory mutation for R263K.
Abstract: Given that different resistance pathways can sometimes synergize to confer high levels of resistance to antiretroviral drugs, we studied the effects of E157Q in association with R263K.
Abstract: RESULTS: E157Q alone had little if any effect on the biochemical activity of IN
Antiviral Activity of Bictegravir (GS-9883), a Novel Potent HIV-1 Integrase Strand Transfer Inhibitor with an Improved Resistance Profile.
PMID: 27645238
2016
Antimicrobial agents and chemotherapy
Result: At the subsequent final P10 day 202, M50I was added to R263K and S119R.
Result: Both R263K and M50I variants are low-frequency natural polymorphisms of HIV-1 IN.
Result: By P9 day 181, 100% of the viruses contained the M50I/R263K double mutant by clonal sequencing.
Result: Clonal sequencing of this P5 virus revealed that even though both S153Y and R263K were detected by population sequencing, no clone actually linked the two mutants.
Result: During the selection with DTG, mutations S153Y and R263K emerged simultaneously at P4 day 87, follow
Prevalence of Integrase Strand Transfer Inhibitors (INSTI) Resistance Mutations in Taiwan.
Method: Besides these three major mutations, the integrase substitutions with a Stanford HIVdb score 10 to at least one INSTI were include
Discussion: Besides the Q148 mutation combined with one or more of G140A/C/S, L74I and E138A/K/T was identified to reduce viral susceptibility to dolutegravir, two amino acid mutations, G118R and R263K, have been reported to confer low-level resistance to dolutegravir.
Discussion: In our study, we did not identify any G118R substitution in our specimens, yet the prevalence of R263K was 0.31% and 1.64% in INSTI-naive and raltegravir-experienced patients, respectively.
Differential effects of the G118R, H51Y, and E138K resistance substitutions in different subtypes of HIV integrase.
Abstract: Additionally, in integrase inhibitor-experienced patients, only R263K and other previously known integrase resistance substitutions have been reported.
Abstract: Unexpectedly, a mutation rarely selected in this scenario (R263K) induces a fitness cost that prevents HIV-1 from evading drug pressure, and accumulation of further secondary mutations does not occur and has not been able to compensate the replication capacity deficit in the aftermath of the appearance of a single drug resistance mutation.
Simian-tropic HIV as a model to study drug resistance against integrase inhibitors.
PMID: 25583721
2015
Antimicrobial agents and chemotherapy
Abstract: Here, we used a T-cell-tropic SIV/HIV recombinant virus in which the capsid and vif regions of HIV-1 were replaced with their SIV counterparts (simian-tropic HIV-1 [stHIV-1](SCA,SVIF)) to study the impact of a number of drug resistance substitutions in the integrase coding region at positions E92Q, G118R, E138K, Y143R, S153Y, N155H, and R263K on drug resistance, viral infectivity, and viral replication capacity.
HIV mutation literature information.
PMID: 
2017
Journal of virology
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