Recruitment of phosphatidylinositol 3-kinase to CD28 inhibits HIV transcription by a Tat-dependent mechanism

J Immunol. 2002 Jul 1;169(1):254-60. doi: 10.4049/jimmunol.169.1.254.

Abstract

Activation through the TCR and the costimulatory molecule CD28 influences the susceptibility of T cells to HIV-1 infection and regulates proviral gene expression. Signaling events initiated by CD28 that directly impact HIV-1 transcription have not been fully characterized. T cell lines expressing CD8alpha/28 chimeric receptors containing a mutation in tyrosine 173 to phenylalanine, which inhibits the recruitment of phosphatidylinositol 3-kinase (PI3K) to CD28, expressed higher levels of HIV-1 following T cell activation. Whereas constitutively active PI3K decreased provirus transcription, inhibiting endogenous PI3K with specific inhibitors or by overexpressing PTEN phosphatase enhanced HIV-1 expression. PI3K-dependent inhibition required the viral Tat protein and a trans activation response region element. Tat pull-down and coimmunoprecipitation experiments indicate that PI3K affects the formation of the Tat-associated kinase trans-activating complex. These studies demonstrate that PI3K negatively impacts HIV-1 transcription and that Tat activity is sensitive to T cell signaling events.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antiviral Agents / genetics
  • Antiviral Agents / physiology*
  • CD28 Antigens / genetics
  • CD28 Antigens / immunology
  • CD28 Antigens / metabolism
  • CD28 Antigens / physiology*
  • CHO Cells
  • Cell Line
  • Cricetinae
  • Down-Regulation / genetics
  • Down-Regulation / immunology
  • Enzyme Activation / genetics
  • Enzyme Inhibitors / pharmacology
  • Gene Products, tat / antagonists & inhibitors*
  • Gene Products, tat / physiology*
  • HIV-1 / genetics*
  • Humans
  • Jurkat Cells
  • Mutagenesis, Site-Directed
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphatidylinositol 3-Kinases / physiology*
  • Phosphoinositide-3 Kinase Inhibitors
  • Proviruses / genetics
  • Proviruses / metabolism
  • Signal Transduction / genetics
  • Signal Transduction / immunology*
  • Transcription, Genetic / immunology*
  • Up-Regulation / genetics
  • Up-Regulation / immunology
  • tat Gene Products, Human Immunodeficiency Virus

Substances

  • Antiviral Agents
  • CD28 Antigens
  • Enzyme Inhibitors
  • Gene Products, tat
  • Phosphoinositide-3 Kinase Inhibitors
  • tat Gene Products, Human Immunodeficiency Virus