The mTOR Complex Controls HIV Latency

Cell Host Microbe. 2016 Dec 14;20(6):785-797. doi: 10.1016/j.chom.2016.11.001.

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.

Keywords: HIV LTR; HIV latency; HIV transcription; genome-wide shRNA screen; latency reversal; mTOR inhibition; reactivation from latency.

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • CD4-Positive T-Lymphocytes / metabolism
  • CD4-Positive T-Lymphocytes / virology
  • Cell Line
  • Clustered Regularly Interspaced Short Palindromic Repeats
  • Cyclin-Dependent Kinase 9 / metabolism
  • Gene Expression Regulation, Viral
  • Gene Knockdown Techniques
  • Genes, Viral
  • HIV Infections / virology*
  • HIV-1 / drug effects*
  • HIV-1 / genetics*
  • HIV-1 / physiology
  • Humans
  • K562 Cells
  • Phosphorylation
  • Positive Transcriptional Elongation Factor B / metabolism
  • RNA, Small Interfering / genetics
  • Signal Transduction
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism
  • TOR Serine-Threonine Kinases / pharmacology*
  • Transcription, Genetic / drug effects
  • Virus Latency / drug effects*
  • mTOR Associated Protein, LST8 Homolog
  • tat Gene Products, Human Immunodeficiency Virus

Substances

  • Adaptor Proteins, Signal Transducing
  • MLST8 protein, human
  • RNA, Small Interfering
  • mTOR Associated Protein, LST8 Homolog
  • tat Gene Products, Human Immunodeficiency Virus
  • TOR Serine-Threonine Kinases
  • Positive Transcriptional Elongation Factor B
  • CDK9 protein, human
  • Cyclin-Dependent Kinase 9