Abstract
Sufficient drug concentrations are required for efficacy of antiretroviral drugs used in human immunodeficiency virus (HIV) care and prevention. Measurement of nucleotide analogs, included in most HIV medication regimens, enables monitoring of short- and long-term adherence and the risk of treatment failure. The REverSe TRanscrIptase Chain Termination (RESTRICT) assay rapidly infers the concentration of intracellular nucleotide analogs based on the inhibition of DNA synthesis by HIV reverse transcriptase (RT) enzyme. Here, we introduce a probabilistic predictive model for RESTRICT and demonstrate selective measurement of multiple nucleotide analogs using DNA templates designed according to the chemical structure of each drug. We measure clinically relevant concentrations of tenofovir diphosphate (TFV-DP), emtricitabine triphosphate (FTC-TP), and azidothymidine triphosphate (AZT-TP) with agreement between experiment and theory. RESTRICT represents a new class of activity-based assays for therapeutic drug monitoring and precision dosing in HIV care and could be extended to other diseases treated with nucleotide analogs.
Supplementary weblinks
Title
All data and code used in the analyses are available on Zenodo
Description
This data set contains all experimental and theoretical data included in the manuscript " REverSe TRanscrIptase Chain Termination (RESTRICT) for Selective Measurement of Nucleotide Analogs Used in HIV Care and Prevention", namely:
RESTRICT_model: MATLAB script for completing calculations in the RESTRICT theoretical model.
Figure 2:
- Raw data from theoretical model showing contributions of individual model components, Kaff = 0.3
- Normalized data from theoretical model showing contributions of individual model components, Kaff = 0.3
- Experimental NRTI Drug Screen 180 nt TTCA 500 nM dNTP
Figure 3:
- Experiment-dNTP-Concentration-Screen
- Theory-dNTP-Concentration-Screen
- Experiment-Template-Length-Screen
- Theory-Template-Length-Screen
- Experiment-Sequence-Screen
- Theory-Sequence-Screen
Figure 4:
- Experimental-NRTI-Drug-Screen-90nt-TCAA-only
- Theory-TCAA90-Kaff=0point2
- Experimental-NRTI-Drug-Screen-GGCA-only
- Theory-GGCA180-Kaff=0point2
Figure 5:
- GGCA-vs-TTCA-Specificity-Analysis
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