ArticleJournal of virology2011
Compensation by the E138K mutation in HIV-1 reverse transcriptase for deficits in viral replication capacity and enzyme processivity associated with the M184I/V mutations.
Article in Journal of virology, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers.
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Who cites it
57 citing papers in PubMed.
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- Design and optimization of piperidine-substituted thiophene[3,2-Acta pharmaceutica Sinica. B · 2024Article
- Recent Advances in Pyrimidine-Based Drugs.Pharmaceuticals (Basel, Switzerland) · 2024Review
- 2022 update of the drug resistance mutations in HIV-1.Topics in antiviral medicine · 2022Article
- Cryo-EM structures of wild-type and E138K/M184I mutant HIV-1 RT/DNA complexed with inhibitors doravirine and rilpivirine.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Exploring the hydrophobic channel of NNIBP leads to the discovery of novel piperidine-substituted thiophene[3,2-Acta pharmaceutica Sinica. B · 2020Article
- 2019 update of the drug resistance mutations in HIV-1.Topics in antiviral medicine · 2019Article
- Molecular and cellular studies evaluating a potent 2-cyanoindolizine catechol diether NNRTI targeting wildtype and Y181C mutant HIV-1 reverse transcriptase.Bioorganic & medicinal chemistry letters · 2019Article
- Assessment of Nonnucleoside Inhibitors Binding to HIV-1 Reverse Transcriptase Using HYDE Scoring.Pharmaceuticals (Basel, Switzerland) · 2019Article
- Article
- Evolutionary footprint of epistasis.PLoS computational biology · 2018Article
- The S230R Integrase Substitution Associated With Virus Load Rebound During Dolutegravir Monotherapy Confers Low-Level Resistance to Integrase Strand-Transfer Inhibitors.The Journal of infectious diseases · 2018Article
- Antiviral Activity of Bictegravir and Cabotegravir against Integrase Inhibitor-Resistant SIVmac239 and HIV-1.Antimicrobial agents and chemotherapy · 2017Article
- M184I/V substitutions and E138K/M184I/V double substitutions in HIV reverse transcriptase do not significantly affect the antiviral activity of EFdA.The Journal of antimicrobial chemotherapy · 2017Article
- What do docking and QSAR tell us about the design of HIV-1 reverse transcriptase nonnucleoside inhibitors?Journal of molecular modeling · 2017Article
- Purification of Zika virus RNA-dependent RNA polymerase and its use to identify small-molecule Zika inhibitors.The Journal of antimicrobial chemotherapy · 2017Article
- Rilpivirine and Doravirine Have Complementary Efficacies Against NNRTI-Resistant HIV-1 Mutants.Journal of acquired immune deficiency syndromes (1999) · 2016Article
- Effect on HIV-1 viral replication capacity of DTG-resistance mutations in NRTI/NNRTI resistant viruses.Retrovirology · 2016Article
- Identification of a Pyridoxine-Derived Small-Molecule Inhibitor Targeting Dengue Virus RNA-Dependent RNA Polymerase.Antimicrobial agents and chemotherapy · 2016Article
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7 authors.
Funding
Abstract
Recently, several phase 3 clinical trials (ECHO and THRIVE) showed that E138K and M184I were the most frequent mutations to emerge in patients who failed therapy with rilpivirine (RPV) together with two nucleos(t)ide reverse transcriptase inhibitors, emtricitabine (FTC) and tenofovir (TDF). To investigate the basis for the copresence of E138K and M184I, we generated recombinant mutated and wild-type (WT) reverse transcriptase (RT) enzymes and HIV-1(NL4-3) infectious clones. Drug susceptibilities were determined in cord blood mononuclear cells (CBMCs). Structural modeling was performed to analyze any impact on deoxynucleoside triphosphate (dNTP) binding. The results of phenotyping showed that viruses containing both the E138K and M184V mutations were more resistant to each of FTC, 3TC, and ETR than viruses containing E138K and M184I. Viruses with E138K displayed only modest resistance to ETR, little resistance to efavirenz (EFV), and no resistance to either FTC or 3TC. E138K restored viral replication capacity (RC) in the presence of M184I/V, and this was confirmed in cell-free RT processivity assays. RT enzymes containing E138K, E138K/184I, or E138K/184V exhibited higher processivity than WT RT at low dNTP concentrations. Steady-state kinetic analysis demonstrated that the E138K mutation resulted in decreased K(m)s for dNTPs. In contrast, M184I/V resulted in an increased K(m) for dNTPs compared to those for WT RT. These results indicate that the E138K mutation compensates for both the deficit in dNTP usage and impairment in replication capacity by M184I/V. Structural modeling shows that the addition of E138K to M184I/V promotes tighter dNTP binding.
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