- Besnard, Emilie;
- Hakre, Shweta;
- Kampmann, Martin;
- Lim, Hyung W;
- Hosmane, Nina N;
- Martin, Alyssa;
- Bassik, Michael C;
- Verschueren, Erik;
- Battivelli, Emilie;
- Chan, Jonathan;
- Svensson, J Peter;
- Gramatica, Andrea;
- Conrad, Ryan J;
- Ott, Melanie;
- Greene, Warner C;
- Krogan, Nevan J;
- Siliciano, Robert F;
- Weissman, Jonathan S;
- Verdin, Eric
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.