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Journal of Virology, November 2006, p. 11141-11152, Vol. 80, No. 22
0022-538X/06/$08.00+0     doi:10.1128/JVI.01556-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Expression of Nef Downregulates CXCR4, the Major Coreceptor of Human Immunodeficiency Virus, from the Surfaces of Target Cells and Thereby Enhances Resistance to Superinfection{triangledown}

Stephanie Venzke, Nico Michel, Ina Allespach, Oliver T. Fackler, and Oliver T. Keppler*

Department of Virology, University of Heidelberg, Heidelberg, Germany

Received 20 July 2006/ Accepted 13 August 2006

Lentiviral Nef proteins are key factors for pathogenesis and are known to downregulate functionally important molecules, including CD4 and major histocompatibility complex class I (MHC-I), from the surfaces of infected cells. Recently, we demonstrated that Nef reduces cell surface levels of the human immunodeficiency virus type 1 (HIV-1) entry coreceptor CCR5 (N. Michel, I. Allespach, S. Venzke, O. T. Fackler, and O. T. Keppler, Curr. Biol. 15:714-723, 2005). Here, we report that Nef downregulates the second major HIV-1 coreceptor, CXCR4, from the surfaces of HIV-infected primary CD4 T lymphocytes with efficiencies comparable to those of the natural CXCR4 ligand, stromal cell-derived factor-1 alpha. Analysis of a panel of mutants of HIV-1SF2 Nef revealed that the viral protein utilized the same signature motifs for downmodulation of CXCR4 and MHC-I, including the proline-rich motif P73P76P79P82 and the acidic cluster motif E66E67E68E69. Expression of wild-type Nef, but not of specific Nef mutants, resulted in a perinuclear accumulation of the coreceptor. Remarkably, the carboxy terminus of CXCR4, which harbors the classical motifs critical for basal and ligand-induced receptor endocytosis, was dispensable for the Nef-mediated reduction of surface exposure. Functionally, the ability of Nef to simultaneously downmodulate CXCR4 and CD4 correlated with maximum-level protection of Nef-expressing target cells from fusion with cells exposing X4 HIV-1 envelopes. Furthermore, the Nef-mediated downregulation of CXCR4 alone on target T lymphocytes was sufficient to diminish cells' susceptibility to X4 HIV-1 virions at the entry step. The downregulation of chemokine coreceptors is a conserved activity of Nef to modulate infected cells, an important functional consequence of which is an enhanced resistance to HIV superinfection.

* Corresponding author. Mailing address: Department of Virology, University of Heidelberg, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany. Phone: 49-6221-565007. Fax: 49-6221-565003. E-mail: oliver_keppler{at}med.uni-heidelberg.de.

{triangledown} Published ahead of print on 23 August 2006.

Journal of Virology, November 2006, p. 11141-11152, Vol. 80, No. 22
0022-538X/06/$08.00+0     doi:10.1128/JVI.01556-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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