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J. Biol. Chem., Vol. 278, Issue 45, 44816-44825, November 7, 2003

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An in Vivo Replication-important Function in the Second Coding Exon of Tat Is Constrained against Mutation despite Cytotoxic T Lymphocyte Selection^*

Stephen M. Smith¶, Sara Pentlicky, Zachary Klase, Mahender Singh, Christine Neuveut||, Chun-yi Lu**, Marvin S. Reitz, Jr., Robert Yarchoan, Preston A. Marx¶¶, and Kuan-Teh Jeang**

From the Saint Michael's Medical Center and The New Jersey Medical School, Newark, New Jersey 07102, ^||Unite de Recombinaison et Expression, Institut Pasteur, 75015 Paris, France, ^**Molecular Virology Section, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, Institute of Human Virology, University of Maryland Biotechnology Institute, Baltimore, Maryland 21201, HIV and AIDS Malignancy Branch, Division of Clinical Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, and ^¶¶Tulane University Health Sciences Center, Department of Tropical Medicine and the Tulane National Primate Research Center, Covington, Louisiana 70433

Human and simian immunodeficiency virus (HIV/SIV) Tat proteins are specified by two coding exons. Tat functions in the transcription of primate lentiviruses. A plethora of in vitro data currently suggests that the second coding exon of Tat is largely devoid of function. However, whether the second exon of Tat contributes functionally to viral pathogenesis in vivo remains unknown. To address this question directly, we compared infection of rhesus macaques with an SIV, engineered to express only the first coding exon of Tat (SIVtat1ex), to counterpart infection with wild-type SIVmac239 virus, which expresses the full 2-exon Tat. This comparison showed that the second coding exon of Tat contributes to chronic SIV replication in vivo. Interestingly, in macaques, we observed a cytotoxic T lymphocytes (CTL) response to the second coding exon of Tat, which appears to durably control SIV replication. When SIV mutated in an attempt to escape this second Tat-exon-CTL, the resulting virus was less replicatively fit and failed to populate the host in vivo. Our study provides the first evidence that the second coding exon in Tat embodies an important function for in vivo replication. We suggest the second coding exon of Tat as an example of a functionally constrained "epitope" whose elicited CTL response cannot be escaped by virus mutation without producing a virus that replicates poorly in vivo.

Received for publication, July 14, 2003 , and in revised form, August 25, 2003.

^* The costs of publication of this article were defrayed in part by payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely

^¶ To whom correspondence should be addressed. Tel.: 973-877-2711; Fax: 973-877-2661; E-mail: stephens{at}cathedralhealth.org.

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