Transient Thresholding: A Mechanism Enabling Noncooperative Transcriptional Circuitry to Form a Switch

Threshold generation in fate-selection circuits is often achieved through deterministic bistability, which requires cooperativity (i.e., nonlinear activation) and associated hysteresis. However, the Tat positive-feedback loop that controls HIV's fate decision between replication and proviral latency lacks self-cooperativity and deterministic bistability. Absent cooperativity, it is unclear how HIV can temporarily remain in an off-state long enough for the kinetically slower epigenetic silencing mechanisms to act—expression fluctuations should rapidly trigger active positive feedback and replication, precluding establishment of latency.

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