Transcriptional Circuit Fragility Influences HIV Proviral Fate.
Cell Rep
; 27(1): 154-171.e9, 2019 04 02.
Article
em En
| MEDLINE
| ID: mdl-30943398
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.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Ativação Viral
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Infecções por HIV
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HIV-1
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Provírus
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Latência Viral
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Redes Reguladoras de Genes
Limite:
Humans
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article