  Noise-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
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.
