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Antimicrobial Agents and Chemotherapy, April 2008, p. 1302-1317, Vol. 52, No. 4
0066-4804/08/$08.00+0     doi:10.1128/AAC.01324-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Inhibition of Human Immunodeficiency Virus Type 1 Replication in Human Cells by Debio-025, a Novel Cyclophilin Binding Agent ^,

Roger G. Ptak,¹ Philippe A. Gallay,² Dirk Jochmans,³ Andrew P. Halestrap,⁴ Urs T. Ruegg,⁵ Luke A. Pallansch,^1, Michael D. Bobardt,² Marie-Pierre de Béthune,³ Johan Neyts,⁶ Erik De Clercq,⁶ Jean-Maurice Dumont,^7* Pietro Scalfaro,⁷ Kamel Besseghir,⁷ Roland M. Wenger,⁸ and Brigitte Rosenwirth⁹

Southern Research Institute, Frederick, Maryland 21701,¹ Department of Immunology, The Scripps Resarch Institute, La Jolla, California 92037,² Tibotec BVBA, 2800 Mechelen, Belgium,³ Department of Biochemistry, University of Bristol, School of Medical Sciences, Bristol BS8 1TD, United Kingdom,⁴ Laboratory of Pharmacology, School of Pharmaceutical Sciences, Universities of Geneva and Lausanne, Geneva 1211, Switzerland,⁵ Rega Institute for Medical Research, Katholieke Universiteit, Leuven 3000, Belgium,⁶ Debiopharm, 1002 Lausanne, Switzerland,⁷ Wenger Chemtech, Riehen 4125, Switzerland,⁸ Klinisches Institut fuer Virologie, Medizinische Universitaet Wien, Vienna 1095, Austria⁹

Received 15 October 2007/ Returned for modification 16 November 2007/ Accepted 16 January 2008

Debio-025 is a synthetic cyclosporine with no immunosuppressive capacity but a high inhibitory potency against cyclophilin A (CypA)-associated cis-trans prolyl isomerase (PPIase) activity. A lack of immunosuppressive effects compared to that of cyclosporine was demonstrated both in vitro and in vivo. For three cyclosporines, the inhibitory potential against PPIase activity was quantitatively correlated with that against human immunodeficiency virus type 1 (HIV-1) replication. Debio-025 selectively inhibited the replication of HIV-1 in a CD4⁺ cell line and in peripheral blood mononuclear cells: potent activity was demonstrated against clinical isolates of various HIV-1 subtypes, including isolates with multidrug resistance to reverse transcriptase and protease inhibitors. Simian immunodeficiency virus and HIV-2 strains were generally resistant to inhibition by Debio-025; however, some notable exceptions of sensitive HIV-2 clinical isolates were detected. In two-drug combination studies, additive inhibitory effects were found between Debio-025 and 19 clinically used drugs of different classes. Clinical HIV-1 isolates that are naturally resistant to Debio-025 and that do not depend on CypA for infection were identified. Comparison of the amino acid sequences of the CypA binding domain of the capsid (CA) protein from Debio-025-sensitive and -resistant HIV-1 isolates indicated that resistance was mostly associated with an H87Q/P exchange. Mechanistically, cyclosporines competitively inhibit the binding of CypA to the HIV-1 CA protein, which is an essential interaction required for early steps in HIV-1 replication. By real-time PCR we demonstrated that early reverse transcription is reduced in the presence of Debio-025 and that late reverse transcription is almost completely blocked. Thus, Debio-025 seems to interfere with the function of CypA during the progression/completion of HIV-1 reverse transcription.

Published ahead of print on 22 January 2008.

Supplemental material for this article may be found at http://aac.asm.org/.

Present address: Cell Trends, Inc., 6 North Church Street, Middletown, MD 21769.