Addition of E138K to R263K in HIV integrase increases resistance to dolutegravir, but fails to restore activity of the HIV integrase enzyme and viral replication capacity.
PMID: 24917583
2014
The Journal of antimicrobial chemotherapy
Abstrac
Abstract: E138K has been identified as a secondary mutation for dolutegravir in selection studies and has also been observed as a secondary mutation in the clinic for the integrase inhibitors raltegravir and elvitegravir.
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.
HIV-1 pol diversity among female bar and hotel workers in Northern Tanzania.
Result: Some subjects harbored multiple secondary mutations (e.g., subject 905 with V90I and E138K) and/or polymorphisms (e.g., subject 237 with A98S and L101Q).The significance of the observed polymorphisms in HIV-1 non-B subtypes is unknown.
Table: E138K
2014 Update of the drug resistance mutations in HIV-1.
Discussion: E138K and to a lesser extent K101E usually occur in combination with the nRTI resistance mutation M184I, which alone does not reduce rilpivirine susceptibility.
Discussion: Cross-resistance studies with raltegravir- and elvitegravir-resistant viruses indicate that Q148H and G140S in combination with mutations L74I/M, E92Q, T97A, E138A/K, G140A, or N155H are associated with 5-fold to 20-fold reduced dolutegravir susceptibility and reduced virologic suppression in patients.
Discussion: Fifteen mutations have been associated with decreased rilp
Fitness impaired drug resistant HIV-1 is not compromised in cell-to-cell transmission or establishment of and reactivation from latency.
Introduction: Further studies have shown that secondary mutations in integrase at positions H51Y and E138K that are associated with R263K failed to restore viral fitness.
Method: Briefly, untreated Jurkat cells were infected through spinoculation with NL4-3-IRES-EGFP, NL4-3-IRES-EGFP-IN(R263K), NL4-3-IRES-EGFP-IN(E138K), NL4-3-IRES-EGFP-IN(E138K/<
Table: E138K
Figure: Only E138K resulted in a decrease in the proportion of infected cells (*); (C) Relative proportion of GFP-expressing reporter proviruses that became reactivated following TNFalpha treatment.
The R263K mutation in HIV integrase that is selected by dolutegravir may actually prevent clinically relevant resistance to this compound.
PMID: 25394027
2014
Journal of the International AIDS Society
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 or E138K are also present.
Abstract: Secondary mutations selected at positions H51Y or E138K did not individually affect either enzyme activity or DTG resistance, but the combination of R263K together with H51Y or E138K increased DTG resistance to about 7-fold accompanied by a 75% loss in each of viral replication capacity, and both in vitro and in vivo integrase activity.
Use of dolutegravir in two INI-experienced patients with multiclass resistance resulted in excellent virological and immunological responses.
PMID: 25397500
2014
Journal of the International AIDS Society
Abstract: Ultra-deep sequencing of integrase showed the selection of Q148R, E138K+Q148K, and N155H variants and phenotypic raltegravir resistance was demonstrated.
Table: E138K
Early clinical response and presence of viral resistant minority variants: a proof of concept study.
PMID: 25397504
2014
Journal of the International AIDS Society
Abstract: One patient without baseline resistance selected for M184I+E138K+T215I (NGS) after four months of TDF/FTC/RPV therapy.
Abstract: Single mutations E138K (two cases) and M184V in three distinct patients and V90I+G190E; M184V+A98S; Y215F+V118I+T215I; L210S+T215I+F227L; and A62V+D67G+K70N+188H in the remaining five subjects.
Rilpivirine resistance mutations in HIV patients failing non-nucleoside reverse transcriptase inhibitor-based therapies.
Abstract: The prevalence of RPV RAMs was K101E (9.1%), K101P (1.4%), E138A (3.9%), E138G (0.3%), E138K (0.3%), E138Q (0.8%), V179L (0.2%), Y181C (21.8%), Y181I (0.5%), Y181V (0.2%), H221Y (8.3%), F227C (0.1%) and M230L (1.5%).
Rilpivirine: a new non-nucleoside reverse transcriptase inhibitor.
PMID: 23099850
2013
The Journal of antimicrobial chemotherapy
Abstract: Seventeen NNRTI mutations have been associated with decreased susceptibility to rilpivirine: K101E/P, E138A/G/K/Q/R, V179L, Y181C/I/V, H221Y, F227C, M230I/L, Y188L and the combination L100I + K103N.
Exploring the molecular mechanism of cross-resistance to HIV-1 integrase strand transfer inhibitors by molecular dynamics simulation and residue interaction network analysis.
PMID: 23231029
2013
Journal of chemical information and modeling
Abstract: On the basis of the homology modeling constructed structure of tetrameric HIV-1 intasome, the detailed molecular mechanism of the cross-resistance mutation E138K/Q148K to three important INSTIs (Raltegravir (RAL, FDA approved in 2007), Elvitegravir (EVG, FDA approved in 2012), and Dolutegravir (DTG, phase III clinical trials)) was investigated by using molecular dynamics (MD) simulation and residue interaction network (RIN) analysis.
HIV mutation literature information.
PMID: 
2014
The Journal of antimicrobial chemotherapy
Browser Board
Co-occurred Entities
Filtrator
ViMRT