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Journal of Virology, May 2009, p. 4854-4860, Vol. 83, No. 10
0022-538X/09/$08.00+0     doi:10.1128/JVI.00187-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

The Human Immunodeficiency Virus Type 2 Vpx Protein Usurps the CUL4A-DDB1^DCAF1 Ubiquitin Ligase To Overcome a Postentry Block in Macrophage Infection ^,

Anna Bergamaschi,^1, Diana Ayinde,^2,3, Annie David,¹ Erwann Le Rouzic,^2,3 Marina Morel,^2,3 Gilles Collin,⁴ Diane Descamps,^4,5 Florence Damond,⁴ Françoise Brun-Vezinet,^4,5 Sebastien Nisole,^2,3 Florence Margottin-Goguet,^2,3 Gianfranco Pancino,^1* and Catherine Transy^2,3*

Institut Pasteur, Unité de Régulation des Infections Rétrovirales, 25 rue du Dr Roux, 75724 Paris Cedex 15, France,¹ Institut Cochin, Université Paris Descartes, CNRS (UMR 8104),² Inserm, U567, 27 rue du Faubourg St Jacques, 75014 Paris, France,³ Laboratoire de Virologie, AP-HP, Hôpital Bichat-Claude Bernard, 75018 Paris, France,⁴ Université Denis Diderot, Paris 7, France⁵

Received 27 January 2009/ Accepted 27 February 2009

The human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) genomes encode several auxiliary proteins that have increasingly shown their importance in the virus-host relationship. One of these proteins, Vpx, is unique to the HIV-2/SIVsm lineage and is critical for viral replication in macrophages. The functional basis for this requirement, as well as the Vpx mode of action, has remained unexplained, and it is all the more enigmatic that HIV type 1 (HIV-1), which has no Vpx counterpart, can infect macrophages. Here, we underscore DCAF1 as a critical host effector of Vpx in its ability to mediate infection and long-term replication of HIV-2 in human macrophages. Vpx assembles with the CUL4A-DDB1 ubiquitin ligase through DCAF1 recruitment. Precluding Vpx present in the incoming virions from recruiting DCAF1 in target macrophages leads to a postentry block characterized by defective accumulation of HIV-2 reverse transcripts. In addition, Vpx from SIVsm functionally complements Vpx-defective HIV-2 in a DCAF1-binding-dependent manner. Altogether, our data point to a mechanism in which Vpx diverts the Cul4A-DDB1^DCAF1 ligase to inactivate an evolutionarily conserved factor, which restricts macrophage infection by HIV-2 and closely related simian viruses.

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* Corresponding author. Mailing address for Gianfranco Pancino: Institut Pasteur, Unité de Régulation des Infections Rétrovirales, 25 rue du Dr Roux, 75724 Paris Cedex 15, France. Phone: 33-1-4568 8738. Fax: 33-1-4568 8957. E-mail: gpancino{at}pasteur.fr. Mailing address for Catherine Transy: Institut Cochin, Inserm, U567, 27 rue du Faubourg St Jacques, 75014 Paris, France. Phone: 33-1-4051 6622. Fax: 33-1-4051 6550. E-mail: catherine.transy{at}inserm.fr

Published ahead of print on 4 March 2009.

Supplemental material for this study may be found at http://jvi.asm.org/.

A.B. and D.A. contributed equally to this study.

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Journal of Virology, May 2009, p. 4854-4860, Vol. 83, No. 10
0022-538X/09/$08.00+0     doi:10.1128/JVI.00187-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.