The Nonequilibrium Mechanism of Noise Enhancer synergizing with Activator in HIV Latency Reactivation

Abstract

21 has become a leading strategy in curing HIV. Recently, single-cell screening experiments 22 have shown the drug synergy between two categories of biomolecules, Activators (AC) 23 and Noise Enhancers (NE): NE can amplify the reactivation of latent HIV induced by AC, 24 although NE itself cannot reactivate HIV latency. Based on an established LTR-two-state 25 effective model, we uncover two necessary conditions for this type of drug synergy: The 26 decreasing of the turning-on rate of LTR induced by NE is highly inhibited when 27 presented with AC; The timescale of LTR turning off without AC/NE presented should be 28 no slower than the timescale of Tat transactivation. Then we propose a detailed LTR-29 four-state mechanistic model with both AC/NE regulation kinetics and Tat transactivation 30 circuit. We show that, in order to achieve drug synergy, the system of HIV gene state 31 transition must operate out of thermodynamic equilibrium, which is caused by energy 32 input. The direction of energy input determines whether the inhibition of NE upon the 33 reactivation rate of LTR-off states (unbinding of RNAP) can be successfully prevented in 34 the presence of AC. The drug synergy can also be significantly enhanced if the energy 35input is appropriately distributed to more than one reaction. Our model reveals a generic 36 nonequilibrium mechanism underpinning the noise enhanced drug synergy, which may 37 apply to identify the same drug synergy on reactivating a diverse class of lentivirus 38 latency. 39Keywords: HIV latency reactivation, drug synergy, nonequilibrium mechanism, 40 Tat transactivation, Markov jump process 41 Significance Statement 42The "kick and kill" strategy has become a promising way to cure HIV by eliminating latent 43 HIV reservoirs, the main barrier to a clinical cure. Two categories of biomolecules, 44 Activators (AC) and Noise Enhancers (NE), have been found to have synergy on 45 reactivating latent HIV (kick strategy). We uncover the underlying non-equilibrium 46 mechanism of such drug synergy by developing mathematical models based on genetic 47 regulatory kinetics. We find that controlling the magnitude and direction of energy input 48 into genetic regulatory kinetics can prevent NE from reducing the turn-on rate of the 49 inactivated gene state in the presence of AC, which produces the synergy. This general 50 nonequilibrium mechanism can be useful for identifying other drug synergies on lentivirus 51 latency reactivation.

Network design principle for robust oscillatory behaviors with respect to biological noise

“…As reactions progress, the molecular numbers would randomly increase or decrease by one at some time point (Figure 1E; see Methods), and the waiting time of the increase and decrease obeys exponential distributions with parameters determined by the production and decay rates in the deterministic model, respectively. This stochastic process can be exactly solved by Gillespie algorithm, which has been widely used in previous studies (Guo et al, 2020;Thattai and van Oudenaarden, 2001;Veliz-Cuba et al, 2015;Zhao et al, 2021); however, the computation cost is high, and thus we use chemical Langevin equations as approximations to reduce the cost (Gillespie, 2000). Although the biological noise in nature usually has the extrinsic and intrinsic components simultaneously, we only consider the case where only one source of noise exists for simplicity, i.e., only extrinsic noise exists or only intrinsic noise exists.…”