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Transcriptional Circuit Fragility Influences HIV Proviral Fate.
- Source :
-
Cell reports [Cell Rep] 2019 Apr 02; Vol. 27 (1), pp. 154-171.e9. - Publication Year :
- 2019
-
Abstract
- 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.<br /> (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Cells, Cultured
Gene Expression Regulation, Viral
Genome, Viral
Genomic Instability physiology
HEK293 Cells
HIV Infections genetics
HIV-1 physiology
Humans
Jurkat Cells
Transcription, Genetic
Virus Replication genetics
Gene Regulatory Networks physiology
HIV Infections virology
HIV-1 genetics
Proviruses genetics
Proviruses physiology
Virus Activation genetics
Virus Latency genetics
Subjects
Details
- Language :
- English
- ISSN :
- 2211-1247
- Volume :
- 27
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Cell reports
- Publication Type :
- Academic Journal
- Accession number :
- 30943398
- Full Text :
- https://doi.org/10.1016/j.celrep.2019.03.007