期刊
CELL HOST & MICROBE
卷 20, 期 6, 页码 785-797出版社
CELL PRESS
DOI: 10.1016/j.chom.2016.11.001
关键词
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资金
- CHRP fellowship
- postdoctoral fellowships of the Jane Coffin Childs Memorial Fund
- UCSF Program for Breakthrough Biomedical Research
- NIH Director's New Innovator Award [DP2 GM119139]
- UCSF CFAR
- NIH [1R01DA030216, 1DP1DA031126, P30AI027763, S10 RR028962]
- NIH/NIAID [R01Ai117864, NIH/NIDA/1R01DA041742-01, NIH/NIDCR/1R01DE026010-01, 5-31532]
- Swedish Research Council [VR-M2015-02312]
- University of California, San Francisco-Gladstone Institute of Virology and Immunology Center for AIDS Research (CFAR)
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.
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