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J. Biol. Chem., Vol. 282, Issue 21, 15743-15753, May 25, 2007

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Interaction between HIV-1 Rev and Integrase Proteins

A BASIS FOR THE DEVELOPMENT OF ANTI-HIV PEPTIDES^*

Joseph Rosenbluh, Zvi Hayouka, Shoshana Loya^¶, Aviad Levin^||, Ayelet Armon-Omer, Elena Britan^||, Amnon Hizi^¶, Moshe Kotler^||, Assaf Friedler¹, and Abraham Loyter²

From the Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, and Department of Organic Chemistry, Institute of Chemistry, The Hebrew University of Jerusalem, Jerusalem 91904, the ^¶Department of Cell and Developmental Biology, The Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, and the ^||Department of Pathology, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel

Human immunodeficiency virus 1 (HIV-1) Rev and integrase (IN) proteins are required within the nuclei of infected cells in the late and early phases of the viral replication cycle, respectively. Here we show using various biochemical methods, that these two proteins interact with each other in vitro and in vivo. Peptide mapping and fluorescence anisotropy showed that IN binds residues 1-30 and 49-74 of Rev. Following this observation, we identified two short Rev-derived peptides that inhibit the 3'-end processing and strand-transfer enzymatic activities of IN in vitro. The peptides bound IN in vitro, penetrated into cultured cells, and significantly inhibited HIV-1 in multinuclear activation of a galactosidase indicator (MAGI) and lymphoid cultured cells. Real time PCR analysis revealed that the inhibition of HIV-1 multiplication is due to inhibition of the catalytic activity of the viral IN. The present work describes novel anti-HIV-1 lead peptides that inhibit viral replication in cultured cells by blocking DNA integration in vivo.

Received for publication, October 19, 2006 , and in revised form, March 29, 2007.

^* This work was supported in part by grants from the Israel Science Foundation, Israel Ministry of Health (to A. L. and M. K.), and Austrian National Bank (to A. L.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S3.

¹ Supported by an institutional Bikura grant from the Israeli Science Foundation.

² To whom correspondence should be addressed. Tel.: 972-2-658-5422; Fax: 972-2-658-6448; E-mail: loyter{at}mail.ls.huji.ac.il.

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