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Originally published In Press as doi:10.1074/jbc.M210164200 on December 11, 2002

J. Biol. Chem., Vol. 278, Issue 8, 6596-6602, February 21, 2003
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Potent Suppression of Viral Infectivity by the Peptides That Inhibit Multimerization of Human Immunodeficiency Virus Type 1 (HIV-1) Vif Proteins*

Bin YangDagger , Ling GaoDagger , Lin LiDagger , Zhixian Lu§, Xuejun Fan§, Charvi A. PatelDagger , Roger J. PomerantzDagger , Garrett C. DuBois§, and Hui ZhangDagger

From the Dagger  The Dorrance H. Hamilton Laboratories, Center for Human Virology, Division of Infectious Diseases, Department of Medicine and § Kimmel Cancer Center, Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107

Virion infectivity factor (Vif) is essential for the replication of human immunodeficiency virus type 1 (HIV-1) in vivo, but its function remains uncertain. Recently, we have shown that Vif proteins are able to form multimers, including dimers, trimers, or tetramers. Because the multimerization of Vif proteins is required for Vif function in the viral life cycle, we propose that it could be a novel target for anti-HIV-1 therapeutics. Through a phage peptide display method, we have identified a set of 12-mer peptides containing a PXP motif that binds to HIV-1 Vif protein. These proline-enriched peptides potently inhibited the Vif-Vif interaction in vitro. We have also screened a set of synthesized Vif peptides (15-mer), which covers all the amino acids of the HIV-1 Vif protein sequence, for their ability to inhibit the Vif-Vif interaction in vitro. We demonstrated that Vif-derived proline-enriched peptides that contain the 161PPLP164 domain are able to inhibit the Vif-Vif interaction. Conversely, the deletion of the 161PPLP164 domain of Vif protein will significantly impair the capability of Vif proteins to interact with each other, indicating that the 161PPLP164 domain plays a key role in Vif multimerization. All these results demonstrate that the proline-enriched peptides block the multimerization of Vif through interfering with the polyproline interfaces of Vif formed by 161PPLP164 domain. Moreover, these peptides which inhibit the Vif-Vif interaction in vitro potently inhibit HIV-1 replication in the "nonpermissive" T-cells. We propose that this study starts a novel strategy to develop structural diverse inhibitors of Vif such as peptidomimetics or small organic molecules.

* This work was supported by National Institutes of Health Grant AI47720 (to H. Z.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: 1020 Locust St., Suite 329, Philadelphia, PA 19107. Tel.: 215-503-0163; Fax: 215-923-1956; E-mail: hui.zhang@mail.tju.edu.

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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