TitleThe mTOR Complex Controls HIV Latency.
Publication TypeJournal Article
Year of Publication2016
AuthorsBesnard E, Hakre S, Kampmann M, Lim HW, Hosmane NN, Martin A, Bassik MC, Verschueren E, Battivelli E, Chan J, J Svensson P, Gramatica A, Conrad RJ, Ott M, Greene WC, Krogan NJ, Siliciano RF, Weissman JS, Verdin E
JournalCell Host Microbe
Volume20
Issue6
Pagination785-797
Date Published2016 Dec 14
ISSN1934-6069
KeywordsAdaptor Proteins, Signal Transducing, CD4-Positive T-Lymphocytes, Cell Line, Clustered Regularly Interspaced Short Palindromic Repeats, Cyclin-Dependent Kinase 9, Gene Expression Regulation, Viral, Gene Knockdown Techniques, Genes, Viral, HIV Infections, HIV-1, Humans, K562 Cells, MTOR Associated Protein, LST8 Homolog, Phosphorylation, Positive Transcriptional Elongation Factor B, RNA, Small Interfering, Signal Transduction, tat Gene Products, Human Immunodeficiency Virus, TOR Serine-Threonine Kinases, Transcription, Genetic, Virus Latency
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.

DOI10.1016/j.chom.2016.11.001
Alternate JournalCell Host Microbe
PubMed ID27978436
PubMed Central IDPMC5354304
Grant ListR01 DA041742 / DA / NIDA NIH HHS / United States
R01 AI117864 / AI / NIAID NIH HHS / United States
DP1 DA031126 / DA / NIDA NIH HHS / United States
S10 RR028962 / RR / NCRR NIH HHS / United States
P50 GM082250 / GM / NIGMS NIH HHS / United States
DP2 GM119139 / GM / NIGMS NIH HHS / United States
P30 AI027763 / AI / NIAID NIH HHS / United States
R01 DE026010 / DE / NIDCR NIH HHS / United States
R01 DA030216 / DA / NIDA NIH HHS / United States
T32 GM008752 / GM / NIGMS NIH HHS / United States