Mapping the architecture of the HIV-1 Tat circuit: A decision-making circuit that lacks bistability and exploits stochastic noise

Upon infection of a CD4+ T cell, HIV-1 appears to ‘choose’ between two alternate fates: active replication or a long-lived dormant state termed proviral latency. A transcriptional positive-feedback loop generated by the HIV-1 Tat protein appears sufficient to mediate this decision. Here, we describe a coupled wet-lab and computational approach that uses mathematical modeling and live-cell time-lapse microscopy to map the architecture of the HIV-1 Tat transcriptional regulatory circuit and generate predictive models of HIV-1 latency. This approach provided the first characterization of a ‘decision-making’ circuit that lacks bistability and instead exploits stochastic fluctuations in cellular molecules (i.e. noise) to generate a decision between an on or off transcriptional state.