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J. Biol. Chem., Vol. 280, Issue 33, 29570-29577, August 19, 2005

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CCR5 N-terminal Region Plays a Critical Role in HIV-1 Inhibition by Toxoplasma gondii-derived Cyclophilin-18^*

Hana Golding, Surender Khurana, Felix Yarovinsky¶, Lisa R. King, Galina Abdoulaeva||, Liselotte Antonsson**, Christer Owman**, Emily J. Platt, David Kabat, John F. Andersen¶¶, and Alan Sher¶

From the Division of Viral Products and ^||Core Facility, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892, ^¶Laboratory of Parasitic Diseases and ^¶¶Laboratory of Malaria and Vector Research, NIAID, National Institutes of Health, Bethesda, Maryland 20892, ^**Division of Molecular Neurobiology, BMC-A12, SE-221 84 Lund, Sweden, and Oregon Health and Sciences University, Portland, Oregon 97239

Molecular mimicry of chemokine ligands has been described for several pathogens. Toxoplasma gondii produces a protein, cyclophilin-18 (C-18), which binds to the human immunodeficiency virus (HIV) co-receptor CCR5 and inhibits fusion and infection of T cells and macrophages by R5 viruses but not by X4 viruses. We recently identified structural determinants of C-18 required for anti-HIV activity (Yarovinsky, F., Andersen, J. F., King, L. R., Caspar, P., Aliberti, J., Golding, H., and Sher, A. (2004) J. Biol. Chem. 279, 53635–53642). Here we have elucidated the fine specificity of CCR5 residues involved in binding and HIV inhibitory potential of C-18. To delineate the regions of CCR5 involved in C-18 binding, we analyzed C-18 inhibition of cells expressing CXCR4/CCR5 chimeric receptors and CCR5 with a truncated N terminus (2–19). These experiments identified a critical role for the N terminus of CCR5 in C-18 binding and anti-HIV activity. Studies with a large panel of CCR5 N-terminal peptides, including Tyr-sulfated analogues, truncated peptides, and alanine-scanning mutants, suggested that each of the 12–17 amino acids in the N terminus of CCR5 are essential for C-18 binding and inhibitory activity. Tyr sulfation did not improve C-18 reactivity. This finding is of interest because the same CCR5 N-terminal region was shown previously to play a key role in binding of HIV-1 envelope glycoproteins. The elucidation of the functional C-18-binding mechanism may help in the rational design of novel antiviral agents against HIV.

Received for publication, January 7, 2005 , and in revised form, June 3, 2005.

^* This work was supported in part by National Institutes of Health Intramural AIDS Targeted Antiviral Program. 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.

Supported by the Network of Inflammation Research funded by the Swedish Foundation Strategic Research.

To whom correspondence should be addressed. Tel.: 301-827-0784; Fax: 301-496-1810; E-mail: goldingh{at}cber.FDA.gov.

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