ArticleRetrovirology2013
Hypersusceptibility mechanism of Tenofovir-resistant HIV to EFdA.
Article in Retrovirology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
28 citing papers in PubMed, 39 citations in OpenAlex.
- Development of Human Immunodeficiency Virus Type 1 Resistance to 4'-Ethynyl-2-Fluoro-2'-Deoxyadenosine Starting with Wild-Type or Nucleoside Reverse Transcriptase Inhibitor-Resistant Strains.Antimicrobial agents and chemotherapy · 2021Trial
- Current evidence on islatravir drug resistance and implications for future HIV treatment.Topics in antiviral medicine · 2026Review
- Unraveling the Mechanism of HIV-1 Hypersusceptibility to Tenofovir Imparted by Islatravir Resistance Mutations.bioRxiv : the preprint server for biology · 2026Article
- Article
- HIV-1 Resistance to Islatravir/Tenofovir Combination Therapy in Wild-Type or NRTI-Resistant Strains of Diverse HIV-1 Subtypes.Viruses · 2023Article
- Broad spectrum antiviral nucleosides-Our best hope for the future.Annual reports in medicinal chemistry · 2021Article
- Next-Generation Preexposure Prophylaxis: Choices For Effective HIV Prevention.The Journal of infectious diseases · 2020Article
- A Subcutaneous Implant of Tenofovir Alafenamide Fumarate Causes Local Inflammation and Tissue Necrosis in Rabbits and Macaques.Antimicrobial agents and chemotherapy · 2020Article
- Design, Synthesis, and Biological Evaluation of EdAP, a 4'-Ethynyl-2'-Deoxyadenosine 5'-Monophosphate Analog, as a Potent Influenza a Inhibitor.Molecules (Basel, Switzerland) · 2019Article
- Long-Acting Anti-HIV Drugs Targeting HIV-1 Reverse Transcriptase and Integrase.Pharmaceuticals (Basel, Switzerland) · 2019Review
- The High Genetic Barrier of EFdA/MK-8591 Stems from Strong Interactions with the Active Site of Drug-Resistant HIV-1 Reverse Transcriptase.Cell chemical biology · 2018Article
- Antiretroviral potency of 4'-ethnyl-2'-fluoro-2'-deoxyadenosine, tenofovir alafenamide and second-generation NNRTIs across diverse HIV-1 subtypes.The Journal of antimicrobial chemotherapy · 2018Article
- 4'-Ethynyl-2-fluoro-2'-deoxyadenosine, MK-8591: a novel HIV-1 reverse transcriptase translocation inhibitor.Current opinion in HIV and AIDS · 2018Review
- Emerging reverse transcriptase inhibitors for HIV-1 infection.Expert opinion on emerging drugs · 2018Review
- Long acting systemic HIV pre-exposure prophylaxis: an examination of the field.Drug delivery and translational research · 2017Review
- MK-8591 (4'-Ethynyl-2-Fluoro-2'-Deoxyadenosine) Exhibits Potent Activity against HIV-2 Isolates and Drug-Resistant HIV-2 Mutants in Culture.Antimicrobial agents and chemotherapy · 2017Article
- Physiological MgBiochemistry · 2017Article
- Derivatives of mesoxalic acid block translocation of HIV-1 reverse transcriptase.The Journal of biological chemistry · 2015Article
- Subtype-specific analysis of the K65R substitution in HIV-1 that confers hypersusceptibility to a novel nucleotide-competing reverse transcriptase inhibitor.Antimicrobial agents and chemotherapy · 2015Article
- The lysine 65 residue in HIV-1 reverse transcriptase function and in nucleoside analog drug resistance.Viruses · 2014Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
14 authors at 5 institutions in 2 countries.
Funding
Abstract
backgroundThe K65R substitution in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) is the major resistance mutation selected in patients treated with first-line antiretroviral tenofovir disoproxil fumarate (TDF). 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA), is the most potent nucleoside analog RT inhibitor (NRTI) that unlike all approved NRTIs retains a 3'-hydroxyl group and has remarkable potency against wild-type (WT) and drug-resistant HIVs. EFdA acts primarily as a chain terminator by blocking translocation following its incorporation into the nascent DNA chain. EFdA is in preclinical development and its effect on clinically relevant drug resistant HIV strains is critically important for the design of optimal regimens prior to initiation of clinical trials.
resultsHere we report that the K65R RT mutation causes hypersusceptibility to EFdA. Specifically, in single replication cycle experiments we found that EFdA blocks WT HIV ten times more efficiently than TDF. Under the same conditions K65R HIV was inhibited over 70 times more efficiently by EFdA than TDF. We determined the molecular mechanism of this hypersensitivity using enzymatic studies with WT and K65R RT. This substitution causes minor changes in the efficiency of EFdA incorporation with respect to the natural dATP substrate and also in the efficiency of RT translocation following incorporation of the inhibitor into the nascent DNA. However, a significant decrease in the excision efficiency of EFdA-MP from the 3' primer terminus appears to be the primary cause of increased susceptibility to the inhibitor. Notably, the effects of the mutation are DNA-sequence dependent.
conclusionWe have elucidated the mechanism of K65R HIV hypersusceptibility to EFdA. Our findings highlight the potential of EFdA to improve combination strategies against TDF-resistant HIV-1 strains.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.