摘要：SummaryNoise-modulating chemicals can synergize with transcriptional activators in reactivating latent HIV to eliminate latent HIV reservoirs. To understand the underlying biomolecular mechanism, we investigate a previous two-gene-state model and identify two necessary conditions for the synergy: an assumption of the inhibition effect of transcription activators on noise enhancers; and frequent transitions to the gene non-transcription-permissive state. We then develop a loop-four-gene-state model with Tat transcription/translation and find that drug synergy is mainly determined by the magnitude and direction of energy input into the genetic regulatory kinetics of the HIV promoter. The inhibition effect of transcription activators is actually a phenomenon of energy dissipation in the nonequilibrium gene transition system. Overall, the loop-four-state model demonstrates that energy dissipation plays a crucial role in HIV latency reactivation, which might be useful for improving drug effects and identifying other synergies on lentivirus latency reactivation.Graphical abstractDisplay OmittedHighlights•The inhibition of Activator on Noise enhancer is necessary for their synergy in reactivating HIV•The drug synergy is a nonequilibrium phenomenon in the gene regulatory system•The magnitude and direction of energy input determine the drug synergy•This nonequilibrium mechanism is general without regarding molecular detailsDrugs; Virology; Mathematical biosciences
