12:00-12:30 lunch；12:30-13:30 Talk

Abstract: Reactivating HIV latency and then simultaneously eliminating it by antiretroviral therapy has become a leading HIV-cure strategy. Recently single-cell screening experiments have shown the synergy between activator (AC) and noise enhancer(NE), two categories of biomolecules: NE can amplify AC reactivating latent HIV, while NE itself cannot reactivate HIV latency, i.e. 1+1>2. Here we propose a mechanistic model containing both AC/NE-DNA binding and positive feedback of Tat circuit, which can successfully reproduce all the core experimental observations. We found out that the AC\NE transcription factor regulation of HIV LTR expression in the drug synergy system must operate out of equilibrium with energy dissipation, found that the specific energy input can produce synergy between AC and NE on the overall transcription rate of LTR when without self-feedback. We used probability tools and demonstrated that these energy input on interaction between AC and NE makes LTR binding RNAP more stable. Besides, we used cell fate Waddington landscape to illustrate the synergy between AC and NE: AC makes the latent state valley on the cell fate landscape shallower and wider, while NE dig out a new valley on the active state. Then in Tat positive-feedback transcription factor regulated model, we found that only when the timescale of DNA unbinding RNAP (LTR turning off) is comparable to the timescale of Tat production under self-positive-feedback, the synergy of AC and NE on the transcription rate P_on at gene state level can pass to protein expression level with self-positive-feedback. Our model reveals a general nonequilibrium mechanism underpinning the noise enhanced drug synergy. Furthermore, such a proposed mechanism should be useful for identifying new drug synergy or regulating the existing drug synergy in the HIV therapy.

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