Transcriptional Circuit Fragility Influences HIV Proviral Fate

Transcriptional circuit architectures can be evolutionarily selected to precisely dictate a given response. Unlike these cellular systems, HIV is regulated through a complex circuit composed of two successive phases (host and viral), which create a positive feedback loop facilitating viral replication. However, it has long remained unclear whether both phases operate identically and to what extent the host phase influences the entire circuit. Here we report that while the host phase is regulated by a checkpoint whereby KAP1 mediates transcription activation, the virus evolved a minimalist system bypassing KAP1. Given the complex circuit architecture, cell-to-cell KAP1 fluctuations impart heterogeneity in the host transcriptional responses thus affecting the feedback loop. Mathematical modeling of a complete circuit reveals how these oscillations ultimately influence homogeneous reactivation potential of a latent virus. Thus, while HIV drives molecular innovation to fuel robust gene activation, it experiences transcriptional fragility thereby influencing viral fate and cure efforts.