ArticlePloS one2011
K70Q adds high-level tenofovir resistance to "Q151M complex" HIV reverse transcriptase through the enhanced discrimination mechanism.
Article in PloS one, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed.
- Mechanistic cross-talk between DNA/RNA polymerase enzyme kinetics and nucleotide substrate availability in cells: Implications for polymerase inhibitor discovery.The Journal of biological chemistry · 2020Review
- Emerging reverse transcriptase inhibitors for HIV-1 infection.Expert opinion on emerging drugs · 2018Review
- Amino acid residues in HIV-2 reverse transcriptase that restrict the development of nucleoside analogue resistance through the excision pathway.The Journal of biological chemistry · 2018Article
- Human Immunodeficiency Virus Type 1 Drug Resistance Mutations Update.The Journal of infectious diseases · 2017Article
- Structural Insights into HIV Reverse Transcriptase Mutations Q151M and Q151M Complex That Confer Multinucleoside Drug Resistance.Antimicrobial agents and chemotherapy · 2017Article
- Mutational Correlates of Virological Failure in Individuals Receiving a WHO-Recommended Tenofovir-Containing First-Line Regimen: An International Collaboration.EBioMedicine · 2017Article
- Modeling the functional state of the reverse transcriptase of hepatitis B virus and its application to probing drug-protein interaction.BMC bioinformatics · 2016Article
- Review
- The lysine 65 residue in HIV-1 reverse transcriptase function and in nucleoside analog drug resistance.Viruses · 2014Review
- 4'-Ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) inhibits HIV-1 reverse transcriptase with multiple mechanisms.The Journal of biological chemistry · 2014Article
- Evaluation of Combinations of 4'-Ethynyl-2-Fluoro-2'-Deoxyadenosine with Clinically Used Antiretroviral Drugs.Antimicrobial agents and chemotherapy · 2013Article
- HIV-1 reverse transcriptase and antiviral drug resistance. Part 2.Current opinion in virology · 2013Review
- Effect of translocation defective reverse transcriptase inhibitors on the activity of N348I, a connection subdomain drug resistant HIV-1 reverse transcriptase mutant.Cellular and molecular biology (Noisy-le-Grand, France) · 2012Article
- HIV-1 reverse transcriptase (RT) polymorphism 172K suppresses the effect of clinically relevant drug resistance mutations to both nucleoside and non-nucleoside RT inhibitors.The Journal of biological chemistry · 2012Article
- Standardized comparison of the relative impacts of HIV-1 reverse transcriptase (RT) mutations on nucleoside RT inhibitor susceptibility.Antimicrobial agents and chemotherapy · 2012Article
- Structural and inhibition studies of the RNase H function of xenotropic murine leukemia virus-related virus reverse transcriptase.Antimicrobial agents and chemotherapy · 2012Article
- In vitro resistance profile of the candidate HIV-1 microbicide drug dapivirine.Antimicrobial agents and chemotherapy · 2012Article
- Biochemical, inhibition and inhibitor resistance studies of xenotropic murine leukemia virus-related virus reverse transcriptase.Nucleic acids research · 2012Article
- The Continuing Evolution of HIV-1 Therapy: Identification and Development of Novel Antiretroviral Agents Targeting Viral and Cellular Targets.Molecular biology international · 2012Article
- Advances in HIV microbicide development.Future medicinal chemistry · 2011Review
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9 authors.
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Abstract
HIV-1 carrying the "Q151M complex" reverse transcriptase (RT) mutations (A62V/V75I/F77L/F116Y/Q151M, or Q151Mc) is resistant to many FDA-approved nucleoside RT inhibitors (NRTIs), but has been considered susceptible to tenofovir disoproxil fumarate (TFV-DF or TDF). We have isolated from a TFV-DF-treated HIV patient a Q151Mc-containing clinical isolate with high phenotypic resistance to TFV-DF. Analysis of the genotypic and phenotypic testing over the course of this patient's therapy lead us to hypothesize that TFV-DF resistance emerged upon appearance of the previously unreported K70Q mutation in the Q151Mc background. Virological analysis showed that HIV with only K70Q was not significantly resistant to TFV-DF. However, addition of K70Q to the Q151Mc background significantly enhanced resistance to several approved NRTIs, and also resulted in high-level (10-fold) resistance to TFV-DF. Biochemical experiments established that the increased resistance to tenofovir is not the result of enhanced excision, as K70Q/Q151Mc RT exhibited diminished, rather than enhanced ATP-based primer unblocking activity. Pre-steady state kinetic analysis of the recombinant enzymes demonstrated that addition of the K70Q mutation selectively decreases the binding of tenofovir-diphosphate (TFV-DP), resulting in reduced incorporation of TFV into the nascent DNA chain. Molecular dynamics simulations suggest that changes in the hydrogen bonding pattern in the polymerase active site of K70Q/Q151Mc RT may contribute to the observed changes in binding and incorporation of TFV-DP. The novel pattern of TFV-resistance may help adjust therapeutic strategies for NRTI-experienced patients with multi-drug resistant (MDR) mutations.
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