The Nef protein of human immunodeficiency virus is a broad-spectrum modulator of chemokine receptor cell surface levels that acts independently of classical motifs for receptor endocytosis and Galphai signaling

Mol Biol Cell. 2006 Aug;17(8):3578-90. doi: 10.1091/mbc.e06-02-0117. Epub 2006 Jun 14.


Chemokine receptors (CKRs) are important physiological mediators of immune defense, inflammatory responses, and angiogenesis, and they have also been implicated in a number of viral disease processes. Here, we report that the Nef protein of human immunodeficiency virus (HIV) reduces cell surface levels of eight different members of the CC- and CXC-family of CKRs by up to 92%. This broad-range activity required specific elements in HIV(SF2) Nef, including the proline-rich motif P73P76P79P82 as well as the acidic cluster motif E66E67E68E69, and Nef expression induced a marked perinuclear accumulation of CKRs. Surprisingly, receptor mutagenesis demonstrated that the cytoplasmic tail of CCR5 and CXCR4, which is critical for basal and ligand-mediated endocytosis, was completely dispensable for this Nef activity. In contrast, triple-mutation of the highly conserved DRY motif in the second intracellular CKR loop abolished the Nef-mediated down-regulation of CXCR4 independently of this motif's role in CKR binding to heterotrimeric G proteins and signaling via the Galphai subunit. Thus, we identify the lentiviral pathogenicity factor Nef as a unique and broad-range modulator of CKR cell surface levels. Nef uses a mechanism that is distinct from well-established pathways orchestrating CKR metabolism and offers an interesting tool to study the multifaceted biology of CKRs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Animals
  • CHO Cells
  • Cell Compartmentation
  • Cricetinae
  • Cricetulus
  • Cytoplasm / metabolism
  • Down-Regulation / genetics
  • Endocytosis*
  • GTP-Binding Protein alpha Subunits, Gi-Go / metabolism*
  • Gene Products, nef / metabolism*
  • HIV-1 / metabolism*
  • HIV-2 / metabolism*
  • HeLa Cells
  • Humans
  • Molecular Sequence Data
  • Protein Transport
  • Receptors, Chemokine / chemistry
  • Receptors, Chemokine / metabolism*
  • Receptors, G-Protein-Coupled / metabolism
  • Signal Transduction*
  • Simian Immunodeficiency Virus / metabolism
  • nef Gene Products, Human Immunodeficiency Virus


  • Gene Products, nef
  • Receptors, Chemokine
  • Receptors, G-Protein-Coupled
  • nef Gene Products, Human Immunodeficiency Virus
  • seven-transmembrane G-protein-coupled receptor
  • GTP-Binding Protein alpha Subunits, Gi-Go