The reservoir of HIV latently infected cells is the major obstacle for eradication of HIV infection. The “shock-and-kill” strategy proposed earlier aims to reduce the reservoir by activating cells out of latency. While the intracellular HIV Tat gene circuit is known to play important roles in controlling latency and its transactivation in HIV-infected cells, the detailed control mechanisms are not well understood. Here we study the mechanism of probabilistic control of the latent and the transactivated cell phenotypes of HIV-infected cells. We reconstructed the probability landscape, which is the probability distribution of the Tat gene circuit states, by directly computing the exact solution of the underlying chemical master equation. Results show that the Tat circuit exhibits a clear bimodal probability landscape (i.e., there are two distinct probability peaks, one associated with the latent cell phenotype and the other with the transactivated cell phenotype). We explore potential modifications to reactions in the Tat gene circuit for more effective transactivation of latent cells (i.e., the shock-and-kill strategy). Our results suggest that enhancing Tat acetylation can dramatically increase Tat and viral production, while increasing the Tat–transactivation response binding affinity can transactivate latent cells more rapidly than other manipulations. Our results further explored the “block and lock” strategy toward a functional cure for HIV. Overall, our study demonstrates a general approach toward discovery of effective therapeutic strategies and druggable targets by examining control mechanisms of cell phenotype switching via exactly computed probability landscapes of reaction networks.

HIV潜伏感染细胞的储存库是根除HIV感染的主要障碍。较早提出的“电击杀”策略旨在通过激活潜伏期的细胞来减少水库。虽然已知细胞内HIV Tat基因电路在控制潜伏期及其在HIV感染的细胞中的反式激活中起着重要作用，但其详细的控制机制仍未得到很好的理解。在这里，我们研究了对HIV感染细胞的潜伏性和反式激活的细胞表型进行概率控制的机制。通过直接计算基础化学主方程的精确解，我们重建了概率图，即Tat基因电路状态的概率分布。结果表明，Tat电路展现出清晰的双峰概率态势（即，有两个不同的概率峰，一个与潜伏细胞表型有关，另一个与反式激活细胞表型有关。我们探索Tat基因电路中反应的潜在修饰，以更有效地激活潜伏细胞（即电击和杀死策略）。我们的结果表明，增强Tat乙酰化可以显着增加Tat和病毒的产生，而增加Tat-transactivation响应结合亲和力则可以比其他操作更快地激活潜伏细胞。我们的研究结果进一步探索了针对艾滋病毒功能治愈的“阻断和锁定”策略。全面的，