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J. Biol. Chem., Vol. 279, Issue 27, 28419-28425, July 2, 2004

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Vpr-mediated Incorporation of UNG2 into HIV-1 Particles Is Required to Modulate the Virus Mutation Rate and for Replication in Macrophages^*

Renxiang Chen, Erwann Le Rouzic¶, Jessica A. Kearney||, Louis M. Mansky||**, and Serge Benichou¶

From the ^||Ohio State University Biochemistry Graduate Program, Columbus, Ohio 43210,Institute for Molecular Virology, University of Minnesota, Minneapolis, Minnesota 55455, and ^¶Institut Cochin, Department of Infectious Diseases, INSERM U567, CNRS UMR8104, Paris, France

Human immunodeficiency virus type 1 is able to infect nondividing cells, such as macrophages, and the viral Vpr protein has been shown to participate in this process. Here, we investigated the impact of the recruitment into virus particles of the nuclear form of uracil DNA glycosylase (UNG2), a cellular DNA repair enzyme, on the virus mutation rate and on replication in macrophages. We demonstrate that the interaction of Vpr with UNG2 led to virion incorporation of a catalytically active enzyme that is directly involved with Vpr in modulating the virus mutation rate. The lack of UNG in virions during virus replication in primary monocyte-derived macrophages further exacerbated virus mutant frequencies to an 18-fold increase compared with the 4-fold increase measured in actively dividing cells. Because the presence of UNG is also critical for efficient infection of macrophages, these observations extend the role of Vpr to another early step of the virus life cycle, e.g. viral DNA synthesis, that is essential for replication of human immunodeficiency virus type 1 in nondividing cells.

Received for publication, April 7, 2004

^* This research was supported by Public Health Service Grant GM56615 (to L. M. M.) and from the French Agency for AIDS Research and SIDACTION (to S. B. and E. L. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

These authors contributed equally to this work.

^** To whom correspondence may be addressed: Institute for Molecular Virology, University of Minnesota, 18-242 Moos Tower, 515 Delaware St. SE, Minneapolis, MN. Tel.: 612-626-5525; Fax: 612-626-5515; E-mail: mansky{at}umn.edu. To whom correspondence may be addressed: Institut Cochin, INSERM U567, Bâtiment Gustave Roussy, 27 Rue du Faubourg Saint-Jacques, 75014 Paris, France. Tel.: 33-1-40-51-65-78; Fax: 33-1-40-51-65-70; E-mail: benichou{at}cochin.inserm.fr.

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