Human immunodeficiency virus reactivation by phorbol esters or T-cell receptor ligation requires both PKCalpha and PKCtheta

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...

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Published inJournal of virology Vol. 79; no. 15; p. 9821
Main Authors Trushin, Sergey A, Bren, Gary D, Asin, Susana, Pennington, Kevin N, Paya, Carlos V, Badley, Andrew D
Format Journal Article
LanguageEnglish
Published United States 01.08.2005
Subjects
Cells, Cultured
HIV-1 - physiology
Humans
Isoenzymes - metabolism
Jurkat Cells
Phorbol Esters - pharmacology
Protein Kinase C - metabolism
Protein Kinase C-alpha
Protein Kinase C-theta
Receptors, Antigen, T-Cell - metabolism
Virus Activation
Virus Latency
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Summary: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 PKCtheta, PKCthetaA148E, and PKCalpha, PKCalphaA25E, induce HIV long terminal repeat (LTR)-dependent transcription in Jurkat and primary human CD4(+) T cells and that both PKCthetaA148E and PKCalphaA25E cause HIV reactivation in J1.1 T cells. Suppression of both PKCalpha and PKCtheta 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 PKCalpha or PKCtheta. Since suppression of PKCalpha and PKCtheta together has no greater inhibitory effect on HIV reactivation than inhibition of PKCalpha alone, our data confirm that PKCalpha and PKCtheta act in sequence. The requirement for PKCalpha and PKCtheta for prostratin-induced HIV reactivation and the ability of selective PKCalpha or PKCtheta agonists to induce HIV transcription indicate that these PKC isoforms are important targets for therapeutic drug design.
ISSN:0022-538X