Transcriptional Circuit Fragility Influences HIV Proviral Fate

• Published in: Cell reports (Cambridge) Vol. 27; no. 1; pp. 154 - 171.e9
• Main Authors: Morton, Emily L., Forst, Christian V., Zheng, Yue, DePaula-Silva, Ana B., Ramirez, Nora-Guadalupe P., Planelles, Vicente, D’Orso, Iván
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 02.04.2019; Elsevier
• Subjects: Cells, Cultured; Gene Expression Regulation, Viral; Gene Regulatory Networks - physiology; Genome, Viral; Genomic Instability - physiology; HEK293 Cells; HIV; HIV Infections - genetics; HIV Infections - virology; HIV-1 - genetics; HIV-1 - physiology; Humans; Jurkat Cells; KAP1; latency; mathematical modeling; P-TEFb; provirus; Proviruses - genetics; Proviruses - physiology; reactivation; stochastic model; Transcription, Genetic; transcriptional regulation; TRIM28; Virus Activation - genetics; Virus Latency - genetics; Virus Replication - genetics; HIV; provirus; KAP1; TRIM28; transcriptional regulation; latency; mathematical modeling; reactivation; stochastic model; P-TEFb
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2019.03.007

Transcriptional circuit architectures in several organisms have been evolutionarily selected to dictate precise given responses. 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, although 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’s 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, although HIV drives molecular innovation to fuel robust gene activation, it experiences transcriptional fragility, thereby influencing viral fate and cure efforts. [Display omitted] •The two phases of the HIV transcriptional circuit have distinct functional requirements•HIV evolved a minimalist program to robustly bypass host cell regulatory checkpoints•Mathematical modeling reveals the host phase is subject to transcriptional fragility•Transcriptional fragility influences the viral feedback and latency reversal potential Morton et al. show that HIV has evolved a minimalist but robust transcriptional circuit that bypasses host regulatory checkpoints. However, they demonstrate that the fragility of the circuit in the host phase (which primes HIV for activation) largely affects proviral transcription and fate.