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.
Original language | English |
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Pages (from-to) | 785-797 |
Number of pages | 13 |
Journal | Cell Host and Microbe |
Volume | 20 |
Issue number | 6 |
DOIs | |
State | Published - 14 Dec 2016 |
Externally published | Yes |
Keywords
- HIV LTR
- HIV latency
- HIV transcription
- genome-wide shRNA screen
- latency reversal
- mTOR inhibition
- reactivation from latency