ArticleRetrovirology2009
Effects of the K65R and K65R/M184V reverse transcriptase mutations in subtype C HIV on enzyme function and drug resistance.
Article in Retrovirology, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 54 citations in OpenAlex.
- Consensus Sequences forViruses · 2025Article
- Treatment Management Challenges in Naïve and Experienced HIV-1-Infected Individuals Carrying the M184V Mutation.Viruses · 2024Review
- HIV-1 Drug Resistance and Genetic Transmission Networks Among MSM Failing Antiretroviral Therapy in South China 2014-2019.Infection and drug resistance · 2021Article
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- Risks and benefits of dolutegravir-based antiretroviral drug regimens in sub-Saharan Africa: a modelling study.The lancet. HIV · 2019Article
- HIV-1 Reverse Transcriptase Promotes Tumor Growth and Metastasis Formation via ROS-Dependent Upregulation of Twist.Oxidative medicine and cellular longevity · 2019Article
- Drug resistance from preferred antiretroviral regimens for HIV infection in South Africa: A modeling study.PloS one · 2019Article
- Twenty-Five Years of Lamivudine: Current and Future Use for the Treatment of HIV-1 Infection.Journal of acquired immune deficiency syndromes (1999) · 2018Review
- Purification of Zika virus RNA-dependent RNA polymerase and its use to identify small-molecule Zika inhibitors.The Journal of antimicrobial chemotherapy · 2017Article
- Effect on HIV-1 viral replication capacity of DTG-resistance mutations in NRTI/NNRTI resistant viruses.Retrovirology · 2016Article
- Should we fear resistance from tenofovir/emtricitabine preexposure prophylaxis?Current opinion in HIV and AIDS · 2016Review
- Identification of a Pyridoxine-Derived Small-Molecule Inhibitor Targeting Dengue Virus RNA-Dependent RNA Polymerase.Antimicrobial agents and chemotherapy · 2016Article
- 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
- Effects of the W153L substitution in HIV reverse transcriptase on viral replication and drug resistance to multiple categories of reverse transcriptase inhibitors.Antimicrobial agents and chemotherapy · 2014Article
- The high cost of fidelity.AIDS research and human retroviruses · 2014Review
- Targeting of the purine biosynthesis host cell pathway enhances the activity of tenofovir against sensitive and drug-resistant HIV-1.The Journal of infectious diseases · 2013Article
- Intersubtype differences in the effect of a rare p24 gag mutation on HIV-1 replicative fitness.Journal of virology · 2012Article
- Article
- The Impact of HIV Genetic Polymorphisms and Subtype Differences on the Occurrence of Resistance to Antiretroviral Drugs.Molecular biology international · 2012Article
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundWe investigated the effects of mutations K65R and K65R plus M184V on enzymatic function and mechanisms of drug resistance in subtype C reverse transcriptase (RT).
methodsRecombinant subtype C HIV-1 RTs containing K65R or K65R+M184V were purified from Escherichia coli. Enzyme activities and tenofovir (TFV) incorporation efficiency by wild-type (WT) and mutant RTs of both subtypes were determined in cell-free assays. Efficiency of (-) ssDNA synthesis and initiation by subtype C RTs was measured using gel-based assays with HIV-1 PBS RNA template and tRNA3Lys as primer. Single-cycle processivity was assayed under variable dNTP concentrations. Steady-state analysis was performed to measure the relative inhibitory capacity (ki/km) of TFV-disphosphate (TFV-DP). ATP-dependent excision and rescue of TFV-or ZDV-terminated DNA synthesis was monitored in time-course experiments.
resultsThe efficiency of tRNA-primed (-)ssDNA synthesis by subtype C RTs was: WT > K65R > K65R+M184V RT. At low dNTP concentration, K65R RT exhibited lower activity in single-cycle processivity assays while the K65R+M184V mutant showed diminished processivity independent of dNTP concentration. ATP-mediated excision of TFV-or ZDV-terminated primer was decreased for K65R and for K65R+M184V RT compared to WT RT. K65R and K65R+M184V displayed 9.8-and 5-fold increases in IC50 for TFV-DP compared to WT RT. The Ki/Km of TFV was increased by 4.1-and 7.2-fold, respectively, for K65R and K65R+M184V compared to WT RT.
conclusionThe diminished initiation efficiency of K65R-containing RTs at low dNTP concentrations have been confirmed for subtype C as well as subtype B. Despite decreased excision, this decreased binding/incorporation results in diminished susceptibility of K65R and K65R+M184 RT to TFV-DP.
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