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.
Figure: Cluster 14947 (a and i) was selected with both dolutegravir and dolutegravir + lamivudine to ascertain the sequential appearance of R263K and M184V.
Discussion: Dolutegravir is a drug for which thein vitro acquisition of singlet substitutions, including R263K, S153Y and H51Y, interfered with further acquisition of secondary resis
The R263K Dolutegravir Resistance-Associated Substitution Progressively Decreases HIV-1 Integration.
Discussion: 1), this suggests that the negative effect of R263K on HIV fitness is exclusively linked to the integration process.
Discussion: Adding to the difficulty of monitoring such cases, we recently reported a transient R263K substitution in the proviral DNA of a chronically infected individual 4 weeks after initiation of DTG-based ART.
Discussion: Additional clinical studies are also needed to study the clinical impact of the R263K substitution on both viral load and viral reservoirs.
Discussion: Alternatively, R263K viruses may be so poorly fit that they may be outcompeted by WT strains upon virological failure.
Discussion: Importantly, our results show no differences in the amounts of both early (minus-strand DNA transfer) and late reverse transcripts that were produced during infections with WT or
Polymorphic substitution E157Q in HIV-1 integrase increases R263K-mediated dolutegravir resistance and decreases DNA binding activity.
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
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.
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
Abstract: A recombinant virus with the BIC-selected M50I/R263K dual mutations in IN exhibited only 2.8-fold reduced susceptibility to BIC compared to wild-type virus.
Figure: Primary INSTI resistance mutations are T66I/A/K, E92Q/G, T97A, Y143C/H/R, S147G, Q148H/K/R, and N155H, and other INSTI resistance mutations are H51Y, L68I/V, V72A/N/T, L74M,
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 included, such as H51Y,
Result: In INSTI-naive patients, the resistance mutations included L74M (n = 28), E92V (1), Q95K (4), T97A (4), E138AK (3), Y143S (1), V151AL (1), N155S (9), E157Q (11), G163K/R (5), S230R (1) and R263K (4) (Supplementary Table 3).
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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