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Vol. 17, Issue 8, 3578-3590, August 2006

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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 G_i Signaling

Department of Virology, University of Heidelberg, D-69120 Heidelberg, Germany

Submitted February 8, 2006; Revised May 31, 2006; Accepted June 1, 2006
Monitoring Editor: Ralph Isberg

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 G_i 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.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

Address correspondence to: Oliver T. Keppler ( oliver_keppler{at}med.uni-heidelberg.de)

Abbreviations used: AP, adaptin; CKR, chemokine receptor; Env, envelope glycoprotein; FBS, fetal bovine serum; GFP, green fluorescent protein; GPCR, G protein-coupled receptor; HIV, human immunodeficiency virus; IRES, internal ribosome entry site; MHC, major histocompatibility class; mRFP, monomeric red fluorescent protein; PACS, phosphofurin acidic cluster sorting protein; PTX, Bordetella pertussis toxin; SH3, src homology-3; SIV, simian immunodeficiency virus; VSV-G, vesicular stomatitis virus glycoprotein.

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