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Cell Host Microbe. 2016 Dec 14;20(6):785-797. doi: 10.1016/j.chom.2016.11.001.

The mTOR Complex Controls HIV Latency.

Author information

1
Gladstone Institute of Virology and Immunology, Gladstone Institutes, San Francisco, CA 94158, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA.
2
Department of Cellular and Molecular Pharmacology, The California Institute for Quantitative Biomedical Research, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
3
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21218, USA.
4
Karolinska Institutet, Department of Biosciences and Nutrition, Novum, 141 83 Huddinge, Sweden.
5
Gladstone Institute of Virology and Immunology, Gladstone Institutes, San Francisco, CA 94158, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94158, USA.
6
Gladstone Institute of Virology and Immunology, Gladstone Institutes, San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, The California Institute for Quantitative Biomedical Research, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
7
Gladstone Institute of Virology and Immunology, Gladstone Institutes, San Francisco, CA 94158, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: everdin@gladstone.ucsf.edu.

Abstract

A population of CD4 T lymphocytes harboring latent HIV genomes can persist in patients on antiretroviral therapy, posing a barrier to HIV eradication. To examine cellular complexes controlling HIV latency, we conducted a genome-wide screen with a pooled ultracomplex shRNA library and in vitro system modeling HIV latency and identified the mTOR complex as a modulator of HIV latency. Knockdown of mTOR complex subunits or pharmacological inhibition of mTOR activity suppresses reversal of latency in various HIV-1 latency models and HIV-infected patient cells. mTOR inhibitors suppress HIV transcription both through the viral transactivator Tat and via Tat-independent mechanisms. This inhibition occurs at least in part via blocking the phosphorylation of CDK9, a p-TEFb complex member that serves as a cofactor for Tat-mediated transcription. The control of HIV latency by mTOR signaling identifies a pathway that may have significant therapeutic opportunities.

KEYWORDS:

HIV LTR; HIV latency; HIV transcription; genome-wide shRNA screen; latency reversal; mTOR inhibition; reactivation from latency

PMID:
27978436
PMCID:
PMC5354304
DOI:
10.1016/j.chom.2016.11.001
[Indexed for MEDLINE]
Free PMC Article

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