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J. Biol. Chem., Vol. 278, Issue 44, 43202-43213, October 31, 2003

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Cyclophilin A Interacts with HIV-1 Vpr and Is Required for Its Functional Expression^*

Kerstin Zander, Michael P. Sherman¶, Uwe Tessmer, Karsten Bruns, Victor Wray||, Alexander T. Prechtel, Evelyn Schubert, Peter Henklein**, Jeremy Luban, Jason Neidleman¶, Warner C. Greene¶, and Ulrich Schubert¶¶||||

From the Heinrich-Pette-Institute of Experimental Virology and Immunology, University of Hamburg, D-20251 Hamburg, Germany, ^¶Gladstone Institute of Virology and Immunology, University of California, San Francisco, California 94103, ^||Department of Molecular Structure Research, Gesellschaft für Biotechnologische Forschung, D-38124 Braunschweig, Germany, ^**Institute of Biochemistry, Humboldt University, D-10115 Berlin, Germany, Departments of Microbiology and Medicine, Columbia University, New York, New York 10018, the Laboratory of Viral Diseases, NIAID, National Institutes of Health, Bethesda, Maryland 20892, and the ^¶¶Institute for Clinical and Molecular Virology, University of Erlangen-Nürnberg, D-91054 Erlangen, Germany

Viral protein R (Vpr) of human immunodeficiency virus, type 1 (HIV-1) is the major virion-associated accessory protein that affects a number of biological functions in the retroviral life cycle, including promotion of the transport of the preintegration complex into the nucleus and the induction of G₂ host cell cycle arrest. Our recent investigation of the conformational heterogeneity of the proline residues in the N terminus of Vpr suggested a functional interaction between Vpr and a host peptidylprolyl cis/trans isomerase (PPIase) that might regulate the cis/trans interconversion of the imidic bond within the conserved proline residues of Vpr in vivo. Using surface plasmon resonance spectroscopy, Far Western blot, and pulldown experiments a physical interaction of Vpr with the major host PPIase cyclophilin A (CypA) is now demonstrated. The interaction domain involves the N-terminal region of Vpr including an essential role for proline in position 35. The CypA inhibitor cyclosporin A and non-immunosuppressive PPIase inhibitors such as NIM811 and sanglifehrin A block expression of Vpr without affecting pre- or post-translational events such as transcription, intracellular transport, or virus incorporation of Vpr. Similarly to CypA inhibition, Vpr expression is also reduced in HIV-1 infected CypA^–/– knock-out T cells. This study thus shows that in addition to the interaction between CypA and HIV-1 capsid occurring during early steps in virus replication, CypA is also important for the de novo synthesis of Vpr and that in the absence of CypA activity, the Vpr-mediated cell cycle arrest is completely lost in HIV-1-infected T cells.

Received for publication, May 23, 2003

^* This work was supported in part by NIAID, National Institutes of Health RO1 Grant AI36199 (to J. L.), by NIDDK, National Institutes of Health RO1 Grant DK59537-01, by Grant Schu11/2-1, by Grant SFB 466-A11, by a Heisenberg grant from the Deutsche Forschungsgemeinschaft, and by Grant IE-S08T06 from the German Human Genome Research Project (to U. S.). 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.

Contributed equally to this work.

^|||| To whom correspondence should be addressed: Inst. for Clinical and Molecular Virology, University of Erlangen-Nürnberg, Schlossgarten 4, 91054 Erlangen, Germany. Tel.: 49-9131-85-26182; Fax: 49-9131-85-22101; E-mail: ulrich.schubert{at}viro.med.uni-erlangen.de.

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