[PDF][PDF] The mTOR complex controls HIV latency

E Besnard, S Hakre, M Kampmann, HW Lim… - Cell host & …, 2016 - cell.com
E Besnard, S Hakre, M Kampmann, HW Lim, NN Hosmane, A Martin, MC Bassik
Cell host & microbe, 2016cell.com
Summary 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 …
Summary
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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