Mechanisms of HIV receptor and co-receptor down-regulation by prostratin: role of conventional and novel PKC isoforms.

Abstract

Prostratin is an unusual non-tumour promoting phorbol ester with potential as an inductive adjuvant therapy for highly active antiretroviral therapy (HAART) due to its ability to up-regulate viral expression from latent provirus. In addition, prostratin is also able to inhibit de novo HIV infection most probably because it induces down-regulation of HIV receptors from the surface of target cells. In this study, we investigate the mechanisms by which prostratin down-regulates HIV receptor and co-receptor surface expression in lymphocytic and monocytic cell lines. Our results indicate that prostratin induces down-regulation of surface expression of CD4 and CXCR4, but not CCR5, in various cell lines. Down-regulation of CD4 and CXCR4 by prostratin is achieved by internalization through receptor-mediated endocytosis and/or macropinocytosis, which is then followed by degradation of these molecules. Because prostratin is a protein kinase C (PKC) activator, we next examined the potential contribution of distinct PKC isoforms to down-regulate CD4 and CXCR4 in response to prostratin stimulation. Although exposure of cells to prostratin or phorbol-myristate-acetate (PMA) induces the translocation of several PKC isoforms to the plasma membrane, the use of specific PKC inhibitors revealed that novel PKCs are the main mediators of the prostratin-induced CD4 down-regulation, whereas both conventional and novel PKCs contribute to CXCR4 down-regulation. Altogether these results showed that prostratin, through the activation of conventional and/or novel PKC isoforms, rapidly reduces cell surface expression of CD4 and CXCR4, but not CCR5, by inducing their internalization and degradation.

• Authors: Marjan Hezareh, Moulay Ahmed Moukil, Ildiko Szanto, Malgorzata Pondarzewski, Sarah Mouche, Nathalie Cherix, Stephen J Brown, Jean-Louis Carpentier, Michelangelo Foti
• Journal: Antiviral chemistry & chemotherapy (Antivir Chem Chemother) Vol. 15 Issue 4 Pg. 207-22 (Jul 2004) ISSN: 0956-3202 [Print] England
• PMID: 15457682 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CD4 Antigens
• Enzyme Inhibitors
• Isoenzymes
• Phorbol Esters
• Receptors, CCR5
• Receptors, CXCR4
• Receptors, HIV
• prostratin
• Protein Kinase C
• Tetradecanoylphorbol Acetate

Topics

• CD4 Antigens (metabolism)
• Cell Line
• Down-Regulation (drug effects)
• Endocytosis (drug effects)
• Enzyme Inhibitors (pharmacology)
• Humans
• Isoenzymes (antagonists & inhibitors, metabolism)
• Phorbol Esters (pharmacology)
• Protein Kinase C (antagonists & inhibitors, metabolism)
• Protein Transport (drug effects)
• Receptors, CCR5 (metabolism)
• Receptors, CXCR4 (metabolism)
• Receptors, HIV (metabolism)
• T-Lymphocytes (drug effects, metabolism)
• Tetradecanoylphorbol Acetate (pharmacology)