HIV-1 Polymerase Inhibition by Nucleoside Analogs: Cellular- and Kinetic Parameters of Efficacy, Susceptibility and Resistance Selection

摘要: Nucleoside analogs (NAs) are used to treat numerous viral infections and cancer. They compete with endogenous nucleotides (dNTP/NTP) for incorporation into nascent DNA/RNA inhibit replication by preventing subsequent primer extension. To date, an integrated mathematical model that could allow the analysis of their mechanism action, various resistance mechanisms, effect on fitness is still lacking. We present first mechanistic polymerase inhibition NAs takes account reversibility inhibition. Analytical solutions point out cellular- kinetic aspects Our correctly predicts HIV-1 against nucleoside analog reverse transcriptase inhibitors (NRTIs) can be conferred decreasing rate, increasing excision or affinity enzyme. For all analyzed NRTIs combinations, model-predicted macroscopic parameters (efficacy, toxicity) were consistent observations. NRTI efficacy was found greatly vary between distinct target cells. Surprisingly, cells low dNTP/NTP levels may not confer hyper-susceptibility inhibition, whereas high contents likely natural resistance. also allows quantification selective advantage mutations integrating effects drug susceptibility. zidovudine triphosphate (AZT-TP), we predict this advantage, as well minimal concentration required select thymidine-associated (TAMs) highly cell-dependent. The developed studying inherent effects, selection forces epistasis based microscopic data. It readily embedded in extended models complete transcription process, analogous processes other viruses help guide development improve our understanding mechanisms during treatment.