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J. Biol. Chem., Vol. 279, Issue 3, 1720-1728, January 16, 2004

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High Attenuation and Immunogenicity of a Simian Immunodeficiency Virus Expressing a Proteolysis-resistant Inhibitor of NF-B^*

Ileana Quinto¶, Antimina Puca||, Jack Greenhouse**, Peter Silvera**, Jake Yalley-Ogunro**, Mark G. Lewis**, Camillo Palmieri||, Francesca Trimboli, Russ Byrum, Joseph Adelsberger, David Venzon¶¶, Xueni Chen, and Giuseppe Scala

From the Department of Clinical and Experimental Medicine, Medical School, University of Catanzaro, 88100 Catanzaro, Italy, the Department of Biochemistry and Biomedical Technology, Medical School, University "Federico II," 80131 Naples, Italy, the ^**Southern Research Institute, Frederick, Maryland 21701, Bioqual, Rockville, Maryland 20850, Science Applications International Corporation-Frederick Inc., National Cancer Institute Frederick, Maryland 21702, and the ^¶¶Biostatistics and Data Management Section, NCI, National Institutes of Health, Bethesda, Maryland 20892

NF-B/IB proteins play a major role in the transcriptional regulation of human immunodeficiency virus, type-1 (HIV-1). In the case of simian immunodeficiency virus (SIV) the cellular factors required for the viral transcriptional activation and replication in vivo remain undefined. Here, we demonstrate that the p50/p65 NF-B transcription factors enhanced the Tat-mediated transcriptional activation of SIVmac239. In addition, IB-S32/36A, a proteolysis-resistant inhibitor of NF-B, strongly inhibited the Tat-mediated transactivation of SIVmac239. Based on this evidence, we have generated a self-regulatory virus by endowing the genome of SIV-mac239 with IB-S32/36A; the resulting virus, SIVIB-S32/36A, was nef-deleted and expressed the NF-B inhibitor. We show that SIVIB-S32/36A was highly and stably attenuated both in cell cultures and in vivo in rhesus macaque as compared with a nef-deleted control virus. Moreover, the high attenuation was associated with a robust immune response as measured by SIV-specific antibody production, tetramer, and intracellular IFN- staining of SIV gag-specific T cells. These results underscore the crucial role of NF-B/IB proteins in the regulation of SIV replication both in cell cultures and in monkeys. Thus, inhibitors of NF-B could efficiently counteract the SIV/HIV replication in vivo and may assist in developing novel approaches for AIDS vaccine and therapy.

Received for publication, August 25, 2003 , and in revised form, October 24, 2003.

^* 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. 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.

^|| Recipients of a fellowship from Fondazione Italiana per la Ricerca sul Cancro.

^¶ To whom correspondence should be addressed. Tel.: 39-081-7463157; Fax: 39-081-7463150; E-mail: quinto{at}dbbm.unina.it.

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