Stochastic analysis of genetic feedback circuit controlling HIV cell-fate decision

Abstract

After infecting a CD4+ T cell, Human Immunodeficiency Virus (HIV) can either replicate and kill the cell or enter latency, a dormant state of the virus where viral gene-expression is turned OFF. Experimental work has shown that a genetic positive feedback circuit under the control of a key HIV regulatory protein, Tat, critically influences this cell fate decision between viral replication and latency. Here, we build and analyze a stochastic model of this genetic feedback circuit. Interestingly, although the deterministic model of this circuit lacks bistability, the stochastic model can exhibit bimodal distributions of Tat levels. The modes of this bimodal distribution correspond to an ON (high Tat level) and OFF (low Tat level) state of the circuit and can be interpreted as different fates of the infected cell. For the proposed stochastic model, we find regions of the parameter space where this genetic feedback circuit exhibits unimodal and bimodal distributions of Tat levels. Our analysis predicts that in physiologically relevant parameter regimes the Tat feedback circuit will exhibit bimodality, consistent with experimental observations. In summary, results presented here provide important insights into the functioning of this essential HIV feedback circuit and shows how circuit parameters can be perturbed to bias the viral cell fate decision at the single-cell level.