HIV-1 Tat Protein Upregulates Inflammatory Mediators and Induces Monocyte Invasion Into the Brain

Mol Cell Neurosci. 2003 Sep;24(1):224-37. doi: 10.1016/s1044-7431(03)00171-4.

Abstract

Impaired inflammatory functions may be critical factors in the mechanisms by which HIV-1 enters the CNS. Evidence indicates that a viral gene product, the protein Tat, can markedly contribute to these effects. In the present study we tested the hypothesis that Tat can upregulate the expression of inflammatory cytokines and adhesion molecules and facilitate the entry of monocytes into the brain. Expression of inflammatory mediators such as monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-alpha), vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1) was assessed in C57BL/6 mice injected with Tat(1-72) into the right hippocampus. In the Tat(1-72)-injected groups, mRNA and protein levels of MCP-1, TNF-alpha, VCAM-1, and ICAM-1 were markedly elevated compared to those in control animals. The most pronounced changes were observed in and around the injected hippocampus. Double-labeling immunohistochemistry demonstrated that inflammatory proteins were primarily expressed in activated microglial cells and perivascular cells. In addition, astrocytes and endothelial cells were susceptible to Tat(1-72)-induced inflammatory responses. These changes were associated with a substantial infiltration of monocytes into the brain. These data demonstrate that intracerebral administration of Tat can induce profound proinflammatory effects in the brain, leading to monocyte infiltration.

Publication types

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

MeSH terms

  • AIDS Dementia Complex / immunology
  • AIDS Dementia Complex / metabolism*
  • AIDS Dementia Complex / physiopathology
  • Animals
  • Blood-Brain Barrier / drug effects
  • Blood-Brain Barrier / immunology
  • Brain / immunology
  • Brain / metabolism
  • Cell Adhesion Molecules / genetics
  • Cell Adhesion Molecules / immunology
  • Cell Adhesion Molecules / metabolism
  • Chemotaxis, Leukocyte / drug effects*
  • Chemotaxis, Leukocyte / immunology
  • Encephalitis / immunology
  • Encephalitis / metabolism*
  • Endothelium, Vascular / immunology
  • Endothelium, Vascular / metabolism
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / immunology
  • Gene Products, tat / immunology
  • Gene Products, tat / metabolism
  • Gene Products, tat / pharmacology*
  • HIV-1 / immunology
  • HIV-1 / metabolism*
  • Inflammation Mediators / immunology
  • Inflammation Mediators / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Monocytes / immunology
  • Neuroglia / drug effects
  • Neuroglia / immunology
  • Neuroglia / metabolism
  • Peptide Fragments / immunology
  • Peptide Fragments / metabolism
  • Peptide Fragments / pharmacology
  • RNA, Messenger / drug effects
  • RNA, Messenger / metabolism
  • Up-Regulation / immunology
  • tat Gene Products, Human Immunodeficiency Virus

Substances

  • Cell Adhesion Molecules
  • Gene Products, tat
  • Inflammation Mediators
  • Peptide Fragments
  • RNA, Messenger
  • tat Gene Products, Human Immunodeficiency Virus