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J. Biol. Chem., Vol. 280, Issue 48, 40293-40300, December 2, 2005

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Naturally Occurring Capsid Substitutions Render HIV-1 Cyclophilin A Independent in Human Cells and TRIM-cyclophilin-resistant in Owl Monkey Cells^*

Udayan Chatterji, Michael D. Bobardt, Robyn Stanfield, Roger G. Ptak¶, Luke A. Pallansch¶, Priscilla A. Ward¶, Maureen J. Jones¶, Cheryl A. Stoddart||, Pietro Scalfaro**, Jean-Maurice Dumont**, Kamel Besseghir**, Brigitte Rosenwirth, and Philippe A. Gallay1

From the Departments of Immunology and Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, the ^¶Department of Infectious Disease Research, Southern Research Institute, Frederick, Maryland 21701, the ^||Gladstone Institute of Virology and Immunology, University of California San Francisco, San Francisco, California 94103, ^**Debiopharm, Chemin Messidor 5-7, Case postale 5911, 1002 Lausanne, Switzerland, and the Department of Virology, Biomedical Primate Research Centre, 2280 GH Rijswijk, The Netherlands

In this study, we asked if a naturally occurring HIV-1 variant exists that circumvents CypA dependence in human cells. To address this issue, we sought viruses for CypA independence using Debio-025, a cyclosporine A (CsA) analog that disrupts CypA-capsid interaction. Surprisingly, viral variants from the Main group replicate even in the presence of the drug. Sequencing analyses revealed that these viruses encode capsid substitutions within the CypA-binding site (V86P/H87Q/I91V/M96I). When we introduced these substitutions into viruses that normally rely on CypA for replication, these mutants no longer depended on CypA, suggesting that naturally occurring capsid substitutions obviate the need for CypA. This is the first demonstration that isolates from the Main group naturally develop CypA-independent strategies to replicate in human cells. Surprisingly, we found that these capsid substitutions render HIV-1 capable of infecting Owl monkey (OMK) cells that highly restrict HIV-1. OMK cell resistance to HIV-1 is mediated via TRIM-Cyp, which arose from a retrotransposition of CypA into the TRIM5 gene. Interestingly, saturation experiments suggest that the Pro⁸⁶/Gln⁸⁷/Val⁹¹/Ile⁹⁶ capsid core is "invisible" to TRIM-Cyp. This study demonstrates that specific capsid substitutions can release HIV-1 from both CypA dependence in human cells and TRIM-Cyp restriction in monkey cells.

Received for publication, June 9, 2005 , and in revised form, September 19, 2005.

^* This work was supported by U.S. Public Health Services Grant AI-046958 (to P. G.) and by NIAID, National Institutes of Health, Department of Health and Human Services Grant N01-AI-25478. This is publication no. 16716-IMM from the Department of Immunology, The Scripps Research Institute, La Jolla, CA. 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.

¹ To whom correspondence should be addressed: Dept. of Immunology IMM-9, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037. Tel.: 858-784-8180; Fax: 858-784-8227; E-mail: gallay{at}scripps.edu.

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