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Feedback control systems are categorized in various ways based on their design, analysis, and signal types.
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Nonlatching positive feedback enables robust bimodality by decoupling expression noise from the mean.

Brandon S Razooky1,2,3,4,5, Youfang Cao6,7, Maike M K Hansen2

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HIV's Tat protein drives bimodal gene expression, enabling the virus to switch between active replication and latency. This positive feedback mechanism optimizes viral fitness and survival.

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Area of Science:

  • Molecular Biology
  • Virology
  • Systems Biology

Background:

  • Biological decision-making relies on generating bimodal expression patterns, with two distinct states coexisting.
  • Understanding the mechanisms behind bimodality is crucial for deciphering cellular fate decisions, particularly in viral infections like HIV.

Purpose of the Study:

  • To investigate the sources of gene expression bimodality in the human immunodeficiency virus (HIV) transcriptional program.
  • To elucidate how HIV controls its fate decision between active replication and latent states through transcriptional regulation.

Main Methods:

  • Combined single-cell analysis with mathematical modeling to study HIV gene expression dynamics.
  • Examined the role of the HIV transactivator of transcription (Tat) protein and its interaction with the long terminal repeat (LTR) promoter.
  • Utilized both minimal synthetic viral circuits and full-length HIV for experimental validation.

Main Results:

  • HIV's Tat protein induces bimodal ON-OFF expression by manipulating the LTR promoter's intrinsic toggling.
  • Transcriptional positive feedback from Tat expands and shifts the LTR promoter's bimodality regime.
  • The Tat circuit's noncooperative feedback architecture is optimized to slow promoter toggling and generate bimodality via stochastic Tat extinction, dampening the noise-mean relationship.

Conclusions:

  • The Tat-mediated positive feedback circuit robustly generates bimodality, decoupling expression noise from mean levels, which likely enhances HIV fitness by facilitating decisions between replication and latency.
  • Positive feedback circuits may have evolved for robust bimodality generation, not just signal amplification, by maintaining stochastic expression despite varying mean levels.
  • These findings offer insights into viral evolution strategies and the broader principles of gene regulatory network design.