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J. Biol. Chem., Vol. 279, Issue 23, 24141-24151, June 4, 2004

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De Novo Design of Peptide Immunogens That Mimic the Coiled Coil Region of Human T-cell Leukemia Virus Type-1 Glycoprotein 21 Transmembrane Subunit for Induction of Native Protein Reactive Neutralizing Antibodies^*

Roshni Sundaram¶, Marcus P. Lynch¶, Sharad V. Rawale¶, Yiping Sun||, Mirdad Kazanji, and Pravin T. P. Kaumaya**¶¶||||**

From the Peptide and Protein Engineering Laboratory, Department of Obstetrics and Gynecology, Division of Vaccine Research, The Ohio State University, Columbus, Ohio 43210, ^**College of Medicine, Arthur G. James Comprehensive Cancer Center, Molecular and Cellular Biochemistry, ^¶¶Center for Retrovirus Research, ^||||Department of Molecular Virology, Immunology, and Medical Genetics, and Department of Microbiology The Ohio State University, Columbus, Ohio 43210, and ^||Corporate Research Division, Miami Valley Laboratories, The Proctor and Gamble Co., Cincinnati, Ohio 45253

Peptide vaccines able to induce high affinity and protective neutralizing antibodies must rely in part on the design of antigenic epitopes that mimic the three-dimensional structure of the corresponding region in the native protein. We describe the design, structural characterization, immunogenicity, and neutralizing potential of antibodies elicited by conformational peptides derived from the human T-cell leukemia virus type 1 (HTLV-1) gp21 envelope glycoprotein spanning residues 347–374. We used a novel template design and a unique synthetic approach to construct two peptides (WCCR2T and CCR2T) that would each assemble into a triple helical coiled coil conformation mimicking the gp21 crystal structure. The peptide B-cell epitopes were grafted onto the side chains of three lysyl residues on a template backbone construct consisting of the sequence acetyl-XGKGKGKGCONH2 (where X represents the tetanus toxoid promiscuous T cell epitope (TT) sequence 580–599). Leucine substitutions were introduced at the a and d positions of the CCR2T sequence to maximize helical character and stability as shown by circular dichroism and guanidinium hydrochloride studies. Serum from an HTLV-1-infected patient was able to recognize the selected epitopes by enzyme-linked immunosorbent assay (ELISA). Mice immunized with the wild-type sequence (WCCR2T) and the mutant sequence (CCR2T) elicited high antibody titers that were capable of recognizing the native protein as shown by flow cytometry and whole virus ELISA. Sera and purified antibodies from immunized mice were able to reduce the formation of syncytia induced by the envelope glycoprotein of HTLV-1, suggesting that antibodies directed against the coiled coil region of gp21 are capable of disrupting cell-cell fusion. Our results indicate that these peptides represent potential candidates for use in a peptide vaccine against HTLV-1.

Received for publication, December 3, 2003 , and in revised form, March 25, 2004.

^* This work was supported by National Institutes of Health Grant A140302 (to P. T. P. K.). 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 whom correspondence should be addressed: Suite 316, Tzagournis Medical Research Facility, 420 W. 12th Ave., Columbus, OH 43210. Tel.: 614-292-7028; Fax: 614-292-1135; E-mail: kaumaya.1{at}osu.edu.

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