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J. Biol. Chem., Vol. 278, Issue 37, 35812-35818, September 12, 2003

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CD28-dependent HIV-1 Transcription Is Associated with Vav, Rac, and NF-B Activation^*

Julie A. Cook  , Lee Albacker , Avery August  ¶ and Andrew J. Henderson  ¶ ||

From the Graduate Program in Biochemistry, Microbiology, and Molecular Biology, the Department of Biochemistry and Molecular Biology, and the ^¶Department of Veterinary Sciences, Pennsylvania State University, University Park, Pennsylvania 16802

Activation of HIV-1-infected T cells through the T cell receptor and costimulatory molecule CD28 induces proviral transcription; however, the mechanism behind this enhanced virus expression is unknown. Jurkat T cells and primary CD4⁺ T cells expressing a CD8/CD28 chimeric receptor containing a mutation at tyrosine 200 in the cytoplasmic tail were unable to fully induce HIV-1 proviral transcription in response to CD8/28 receptor cross-linking in comparison to CD28 costimulation. The loss of transactivation seen with the mutant chimeric receptor correlated with a decrease in Vav tyrosine phosphorylation. CD28-dependent activation of HIV-1 transcription also required the GTPase activity of Rac1, which was not activated during costimulation with the mutated receptor. Furthermore, the mutated receptor was unable to induce NF-B DNA binding or transactivation, as demonstrated by electromobility shift assays and HIV-1 long terminal repeat and NF-B-dependent reporter constructs. These studies show that signaling events initiated by tyrosine 200 of CD28 are required for efficient expression of HIV-1 transcription in activated T cells.

Received for publication, March 20, 2003 , and in revised form, June 27, 2003.

^* This work was supported by National Institutes of Health Grants AI46261 (to A. J. H.) and AI051626 (to A. A.). 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.

^|| To whom correspondence should be addressed: Dept. of Veterinary Sciences, 115 Henning Bldg., Pennsylvania State University, University Park, PA 16802. Tel.: 814-863-0340; Fax: 814-863-6140; E-mail: ajh6{at}psu.edu.

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