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J. Biol. Chem., Vol. 282, Issue 51, 37146-37157, December 21, 2007

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IB- Represses the Transcriptional Activity of the HIV-1 Tat Transactivator by Promoting Its Nuclear Export^*

Antimina Puca¹, Giuseppe Fiume¹, Camillo Palmieri, Francesca Trimboli, Francesco Olimpico, Giuseppe Scala, and Ileana Quinto²

From the Department of Biochemistry and Medical Biotechnology, University of Naples "Federico II", 80131 Naples, Italy and the Department of Experimental and Clinical Medicine, University of Catanzaro "Magna Graecia," 88100 Catanzaro, Italy

The long terminal repeat of human immunodeficiency virus, type 1 (HIV-1) contains an NF-B enhancer and is potently inhibited by IB-S32/36A, a proteolysis-resistant inhibitor of NF-B transacting factors. The evidence that NF-B is dispensable for HIV-1 expression raises the question of whether IB- represses the HIV-1 transcription by mechanisms distinct from NF-B inhibition. Here, we report that IB- negatively regulates the HIV-1 expression and replication in an NF-B-independent manner by directly binding to Tat, which results in the nuclear export and cytoplasmic sequestration of the viral transactivator. The sequence of IB- required for Tat inhibition spans from amino acids 72 to 287 and includes the nuclear localization signal, the carboxyl-terminal nuclear export signal, and the binding site for the arginine-rich domain of Tat. This novel mechanism of cross-talk between Tat and IB- provides further insights into the mechanisms of HIV-1 regulation and could assist in the development of novel strategies for AIDS therapy.

Received for publication, July 16, 2007 , and in revised form, October 10, 2007.

^* This work was supported by grants from Istituto Superiore di Sanità-National Research Program on AIDS, and Ministero dell'Istruzione, dell'Università e della Ricerca-Fondo per gli Investimenti della Ricerca di Base (FIRB). This work was also supported in part by Fondazione Italiana per la Ricerca sul Cancro and Ministero dell'Università e della Ricerca-FIRB fellowships (to A. P., F. T., and G. F.). 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-S5.

¹ These authors contributed equally to this work.

² To whom correspondence should be addressed: Dept. of Experimental and Clinical Medicine, Biosciences Bldg., University of Catanzaro "Magna Graecia," Viale Europa-Germaneto, 88100 Catanzaro, Italy. Tel.: 39-0961-3694057; Fax: 39-0961-3694090; E-mail: quinto{at}unicz.it.

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