Abstract
Fundamental to biological decision-making is the ability to generate
bimodal expression patterns where 2 alternate expression states
simultaneously exist. Here, we use a combination of single-cell analysis
and mathematical modeling to examine the sources of bimodality in the
transcriptional program controlling HIV’s fate decision between active
replication and viral latency. We find that the HIV transactivator of
transcription (Tat) protein manipulates the intrinsic toggling of HIV’s
promoter, the long terminal repeat (LTR), to generate bimodal ON-OFF
expression and that transcriptional positive feedback from Tat shifts
and expands the regime of LTR bimodality. This result holds for both
minimal synthetic viral circuits and full-length virus. Strikingly,
computational analysis indicates that the Tat circuit’s noncooperative
“nonlatching” feedback architecture is optimized to slow the
promoter’s toggling and generate bimodality by stochastic extinction of
Tat. In contrast to the standard Poisson model, theory and experiment
show that nonlatching positive feedback substantially dampens the
inverse noise-mean relationship to maintain stochastic bimodality
despite increasing mean expression levels. Given the rapid evolution of
HIV, the presence of a circuit optimized to robustly generate bimodal
expression appears consistent with the hypothesis that HIV’s decision
between active replication and latency provides a viral fitness
advantage. More broadly, the results suggest that positive-feedback
circuits may have evolved not only for signal amplification but also for
robustly generating bimodality by decoupling expression fluctuations
(noise) from mean expression levels.
