title: The mTOR Complex Controls HIV 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.
authors.affiliation: Gladstone Institute of Virology and Immunology, Gladstone Institutes, San Francisco, CA 94158, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Emilie
authors.initials: E
authors.lastname: Besnard
authors.affiliation: Gladstone Institute of Virology and Immunology, Gladstone Institutes, San Francisco, CA 94158, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Shweta
authors.initials: S
authors.lastname: Hakre
authors.affiliation: Department of Cellular and Molecular Pharmacology, The California Institute for Quantitative Biomedical Research, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Kampmann
authors.affiliation: Gladstone Institute of Virology and Immunology, Gladstone Institutes, San Francisco, CA 94158, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Hyung W
authors.initials: HW
authors.lastname: Lim
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21218, USA.
authors.forename: Nina N
authors.initials: NN
authors.lastname: Hosmane
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21218, USA.
authors.forename: Alyssa
authors.initials: A
authors.lastname: Martin
authors.affiliation: Department of Cellular and Molecular Pharmacology, The California Institute for Quantitative Biomedical Research, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Bassik
authors.affiliation: Department of Cellular and Molecular Pharmacology, The California Institute for Quantitative Biomedical Research, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Erik
authors.initials: E
authors.lastname: Verschueren
authors.affiliation: Gladstone Institute of Virology and Immunology, Gladstone Institutes, San Francisco, CA 94158, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Emilie
authors.initials: E
authors.lastname: Battivelli
authors.affiliation: Gladstone Institute of Virology and Immunology, Gladstone Institutes, San Francisco, CA 94158, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Chan
authors.affiliation: Karolinska Institutet, Department of Biosciences and Nutrition, Novum, 141 83 Huddinge, Sweden.
authors.forename: J Peter
authors.initials: JP
authors.lastname: Svensson
authors.affiliation: Gladstone Institute of Virology and Immunology, Gladstone Institutes, San Francisco, CA 94158, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Gramatica
authors.affiliation: Gladstone Institute of Virology and Immunology, Gladstone Institutes, San Francisco, CA 94158, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Conrad
authors.affiliation: Gladstone Institute of Virology and Immunology, Gladstone Institutes, San Francisco, CA 94158, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Melanie
authors.initials: M
authors.lastname: Ott
authors.affiliation: Gladstone Institute of Virology and Immunology, Gladstone Institutes, San Francisco, CA 94158, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Warner C
authors.initials: WC
authors.lastname: Greene
authors.affiliation: Gladstone Institute of Virology and Immunology, Gladstone Institutes, San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, The California Institute for Quantitative Biomedical Research, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Nevan J
authors.initials: NJ
authors.lastname: Krogan
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21218, USA.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Siliciano
authors.affiliation: Department of Cellular and Molecular Pharmacology, The California Institute for Quantitative Biomedical Research, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Weissman
authors.affiliation: Gladstone Institute of Virology and Immunology, Gladstone Institutes, San Francisco, CA 94158, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: everdin@gladstone.ucsf.edu.
authors.forename: Eric
authors.initials: E
authors.lastname: Verdin
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000821:virology; D002460:Cell Line; D064112:Clustered Regularly Interspaced Short Palindromic Repeats; D042863:Cyclin-Dependent Kinase 9 / Q000378:metabolism; D015967:Gene Expression Regulation, Viral; D055785:Gene Knockdown Techniques; D005814:Genes, Viral; D015658:HIV Infections / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics* / Q000502:physiology; D006801:Humans; D020014:K562 Cells; D010766:Phosphorylation; D042925:Positive Transcriptional Elongation Factor B / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects; D017735:Virus Latency / Q000187:drug effects*; D000076242:mTOR Associated Protein, LST8 Homolog; D054322:tat Gene Products, Human Immunodeficiency Virus
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C555285:MLST8 protein, human; D034741:RNA, Small Interfering; D000076242:mTOR Associated Protein, LST8 Homolog; D054322:tat Gene Products, Human Immunodeficiency Virus; D042925:Positive Transcriptional Elongation Factor B; D058570:TOR Serine-Threonine Kinases; C467969:CDK9 protein, human; D042863:Cyclin-Dependent Kinase 9
keywords: HIV LTR; HIV latency; HIV transcription; genome-wide shRNA screen; latency reversal; mTOR inhibition; reactivation from latency