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J. Biol. Chem., Vol. 278, Issue 34, 32335-32343, August 22, 2003

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A Novel Cyclic Peptide Immunization Strategy for Preventing HIV-1/AIDS Infection and Progression^*

Shogo Misumi  , Masafumi Endo  , Ryouzaburou Mukai ¶, Kuniomi Tachibana ||, Mamoru Umeda ||, Tetsuro Honda ||, Nobutoki Takamune  and Shozo Shoji  **

From the Department of Biochemistry, Faculty of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-Honmachi, Kumamoto, 862-0973, the ^¶Tsukuba Primate Center for Medical Science, National Institute of Infectious Diseases, Tsukuba, Ibaraki 305-0843, and the ^||Research Laboratory, Nissui Pharmaceutical Co., Ltd., Ibaraki 307-0036, Japan

A novel synthetic peptide immunogen targeting the human immunodeficiency virus type-1 (HIV-1) coreceptor CXCR4 was evaluated for its capacity to induce CXCR4-specific antibodies with anti-HIV-1 activity in BALB/c mice and cynomolgus monkeys. A cyclic closed-chain dodecapeptide mimicking the conformation-specific domain of CXCR4 (cDDX4) was prepared in which Gly-Asp, as the dipeptide forming a spacer arm, links the amino and carboxyl termini of the decapeptidyl linear chain (linear DDX4, Asn¹⁷⁶ to Ile¹⁸⁵) derived from the undecapeptidyl arch (UPA; Asn¹⁷⁶ to Cys¹⁸⁶) of extracellular loop 2 (ECL-2) in CXCR4. Immunization of BALB/c mice with cDDX4 conjugated with a multiple-antigen peptide (cDDX4-MAP) induced conformational epitope-specific antibodies, and monoclonal antibody IA2-F9 reacted with cDDX4, but not with linear DDX4, as determined by real-time biomolecular interaction analysis using surface plasmon resonance. The antibody also reacted with cells expressing CXCR4 but not with cells expressing the other HIV coreceptor, CCR5. Furthermore, the antibody inhibited the replication of HIV-1 X4 virus (using CXCR4), as shown by an infection assay using both MAGIC-5 cells and MT4 cells, but not that of HIV-1 R5 virus (using CCR5). The antibody weakly interfered with chemotaxis induced by stromal cell-derived factor-1 in THP-1 cells or moderately inhibited the chemotaxis of Molt4#8 cells under the same conditions. In addition, immunization of cynomolgus monkeys also induced cDDX4-specific antibodies with anti-HIV activity. Taken together, these results indicate that cDDX4 conjugated with a multi-antigen peptide induces the conformational epitope-specific antibodies to the undecapeptidyl arch of CXCR4 may be a novel candidate immunogen for preventing disease progression in HIV-1-infected individuals.

Received for publication, February 4, 2003 , and in revised form, April 30, 2003.

^* This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Health, Labour and Welfare of Japan, and Japan Health Science Foundation. 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.

Both authors contributed equally to this work.

^** To whom correspondence should be addressed. Tel.: 81-96-371-4362; Fax: 81-96-362-7800; E-mail address: shoji{at}gpo.kumamoto-u.ac.jp.

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				D. Nakayama, S. Misumi, R. Mukai, K. Tachibana, M. Umeda, H. Shibata, N. Takamune, and S. Shoji Suppression of Multiclade R5 and X4 Human Immunodeficiency Virus Type-1 Infections by a Coreceptor-Based Anti-HIV Strategy J. Biochem., November 1, 2005; 138(5): 571 - 582. [Abstract] [Full Text] [PDF]