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Human immunodeficiency virus Nef induces rapid internalization of the T-cell coreceptor CD8alphabeta

Veronique Stove1, Inge Van de Walle, Evelien Naessens

  • 1Department of Clinical Chemistry, Microbiology and Immunology, Ghent University Hospita, Belgium.

Journal of Virology
|August 17, 2005
PubMed

Insights

Human immunodeficiency virus (HIV) Nef protein reduces CD8 beta-chain surface levels via endocytosis. Specific mutations in the CD8 beta-chain cytoplasmic tail and HIV Nef protein disrupt this process, indicating shared molecular pathways.

Area of Science:

  • Virology
  • Immunology
  • Molecular Biology

Background:

  • Human immunodeficiency virus (HIV) Nef protein is known to down-regulate surface receptors like CD4, CD28, and MHC class I on infected cells.
  • The precise mechanisms by which Nef affects other immune receptors, such as the CD8alphabeta receptor, are not fully understood.

Purpose of the Study:

  • To investigate the effect of HIV Nef on the surface expression of the CD8alphabeta receptor.
  • To identify the molecular determinants within the CD8 beta-chain and Nef that mediate this down-regulation.

Main Methods:

  • Mutational analysis of the CD8 beta-chain cytoplasmic tail and HIV Nef.
  • Assessment of surface receptor expression using flow cytometry.
  • Investigation of the role of the AP-2 complex in Nef-mediated endocytosis.

Main Results:

  • HIV Nef specifically down-modulates the CD8 beta-chain surface expression through accelerated endocytosis, with less impact on the CD8 alpha-chain.
  • An FMK amino acid motif in the CD8 beta-chain cytoplasmic tail is critical for Nef-induced endocytosis.
  • Mutations affecting CD4 down-regulation in Nef also abrogated CD8 beta-chain endocytosis, suggesting common interaction pathways.
  • Nef-mediated CD8 beta-chain down-regulation is conserved across different HIV and SIV strains and requires an intact AP-2 complex.

Conclusions:

  • HIV Nef utilizes accelerated endocytosis to reduce CD8 beta-chain surface expression, a process dependent on specific motifs in both proteins and the AP-2 complex.
  • These findings reveal conserved molecular interactions between Nef and host cell machinery, potentially contributing to immune system subversion and AIDS progression.

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