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Journal of Virology, September 2005, p. 10978-10987, Vol. 79, No. 17
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.17.10978-10987.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Human Immunodeficiency Virus Type 1 Vpr Induces the Degradation of the UNG and SMUG Uracil-DNA Glycosylases

Bärbel Schröfelbauer,1,2 Qin Yu,1 Samantha G. Zeitlin,3 and Nathaniel R. Landau1*

Infectious Disease Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037,1 University of Natural Resources and Applied Life Sciences, Vienna, Austria, Department of Biotechnology, Institute of Applied Microbiology, Muthgasse 18, A-1180 Vienna, Austria,2 University of California, San Diego, Division of Biological Sciences, La Jolla, CA 920933

Received 4 May 2005/ Accepted 25 May 2005

The human immunodeficiency virus type 1 (HIV-1) accessory protein Vpr has previously been shown to bind to the cellular uracil DNA glycosylase UNG. We show here that the binding of Vpr to UNG and to the related enzyme SMUG induces their proteasomal degradation. UNG and SMUG were found to be encapsidated in {Delta}vpr HIV-1 virions but were significantly less abundant in vpr+ virions. {Delta}vpr virions contained readily detectable uracil-DNA glycosylase enzymatic activity, while the activity was reduced to undetectable levels in vpr+ virions. Consistent with proteasomal degradation, complexes that contained Vpr and the E3 ubiquitin ligase components Cul1 and Cul4 were detected in cell lysates. We hypothesized that the interaction of Vpr might be a means for the virus to reduce the frequency of abasic sites in viral reverse transcripts at uracil residues caused by APOBEC3-catalyzed deamination of cytosine residues. Although APOBEC3 is largely neutralized by the Vif accessory protein, residual enzyme could remain in virions that would generate uracils. In support of this, {Delta}vif vpr+ HIV-1 produced in the presence of limited amounts of APOBEC3G was significantly more infectious than {Delta}vif {Delta}vpr virus. In Addition, vpr+ HIV-1 replicated more efficiently than vpr– virus in cells that expressed limited amounts of APOBEC3G. The findings highlight the importance of cytidine deamination in the virus replication cycle and present a novel function for Vpr.

* Corresponding author. Mailing address: Infectious Disease Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037. Phone: (858) 453-4100. Fax: (858) 554-0341. E-mail: Landau{at}salk.edu.

Journal of Virology, September 2005, p. 10978-10987, Vol. 79, No. 17
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.17.10978-10987.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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