@article{8c3fc6bf4d164c468e2b2274dea06091,
title = "Transcriptional Circuit Fragility Influences HIV Proviral Fate",
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. 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.",
keywords = "HIV, KAP1, P-TEFb, TRIM28, latency, mathematical modeling, provirus, reactivation, stochastic model, transcriptional regulation",
author = "Morton, {Emily L.} and Forst, {Christian V.} and Yue Zheng and DePaula-Silva, {Ana B.} and Ramirez, {Nora Guadalupe P.} and Vicente Planelles and Iv{\'a}n D'Orso",
note = "Funding Information: We are grateful to J. Karn and E. Verdin for generously sharing the J-Lat clones. We apologize to many colleagues whose work could not be cited because of space constrains. Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases (NIAID) of the NIH under award numbers R01AI114362 and R33AI116222 and Welch Foundation grant I-1782 (to I.D.) and by NIAID under award numbers R21AI123035-01 and R33AI122377 (to V.P.) and grant U01AI111598 (to C.V.F.). N.-G.P.R was supported by NIH Pharmacological Sciences Training grant GM007062 and a 2016 pre-doctoral fellowship from the Ford Foundation . Funding Information: We are grateful to J. Karn and E. Verdin for generously sharing the J-Lat clones. We apologize to many colleagues whose work could not be cited because of space constrains. Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases (NIAID) of the NIH under award numbers R01AI114362 and R33AI116222 and Welch Foundation grant I-1782 (to I.D.) and by NIAID under award numbers R21AI123035-01 and R33AI122377 (to V.P.) and grant U01AI111598 (to C.V.F.). N.-G.P.R was supported by NIH Pharmacological Sciences Training grant GM007062 and a 2016 pre-doctoral fellowship from the Ford Foundation. E.L.M. C.V.F. and I.D. conceived the study. A.B.D.P-S. Y.Z. V.P. and I.D. developed the experimental outline for the primary cell model. N.-G.P.R. prepared DNA clones used in this study and assisted E.L.M. in the lentiviral assays and flow cytometry analysis. E.L.M. A.B.D.-S. Y.Z. and I.D. conducted mechanistic studies. A.B.D.P-S. E.L.M, I.D. and Y.Z. conducted primary cell studies. C.V.F. and I.D. developed the mathematical models, performed predictive simulations, and analyzed the outcomes in the context of the experimental data. E.L.M. C.V.F. and I.D. wrote the manuscript with input from all the authors. I.D. is the lead contact, who supervised, guided, and funded the research, with input from V.P. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2019 The Author(s)",
year = "2019",
month = apr,
day = "2",
doi = "10.1016/j.celrep.2019.03.007",
language = "English (US)",
volume = "27",
pages = "154--171.e9",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "1",
}