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Journal of Virology, August 2005, p. 9821-9830, Vol. 79, No. 15
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.15.9821-9830.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Human Immunodeficiency Virus Reactivation by Phorbol Esters or T-Cell Receptor Ligation Requires both PKC and PKC

Sergey A. Trushin,¹ Gary D. Bren,¹ Susana Asin,² Kevin N. Pennington,² Carlos V. Paya,^1,2 and Andrew D. Badley^1*

Division of Infectious Diseases and Program in Translational Immunovirology and Biodefense,¹ Department of Immunology, Mayo Clinic College of Medicine, Rochester, Minnesota²

Received 18 January 2005/ Accepted 27 April 2005

Latently human immunodeficiency virus (HIV)-infected memory CD4⁺ T cells represent the major obstacle to eradicating HIV from infected patients. Antigens, T-cell receptor (TCR) ligation, and phorbol esters can reactivate HIV from latency in a protein kinase C (PKC)-dependent manner; however, it is unknown which specific PKC isoforms are required for this effect. We demonstrate that constitutively active (CA) forms of both PKC, PKCA148E, and PKC, PKCA25E, induce HIV long terminal repeat (LTR)-dependent transcription in Jurkat and primary human CD4⁺ T cells and that both PKCA148E and PKCA25E cause HIV reactivation in J1.1 T cells. Suppression of both PKC and PKC with short hairpinned (sh) RNA inhibited CD3/CD28-induced HIV LTR-dependent transcription and HIV reactivation in J1.1 T cells. Both prostratin and phorbol myristate 13-acetate induced HIV LTR-dependent transcription and HIV reactivation in J1.1 T cells that was blocked by shRNA against either PKC or PKC. Since suppression of PKC and PKC together has no greater inhibitory effect on HIV reactivation than inhibition of PKC alone, our data confirm that PKC and PKC act in sequence. The requirement for PKC and PKC for prostratin-induced HIV reactivation and the ability of selective PKC or PKC agonists to induce HIV transcription indicate that these PKC isoforms are important targets for therapeutic drug design.

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* Corresponding author. Mailing address: Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905. Phone: (507) 284-3747. Fax: (507) 284-3757. E-mail: badley.andrew{at}mayo.edu.

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Journal of Virology, August 2005, p. 9821-9830, Vol. 79, No. 15
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.15.9821-9830.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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