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

Hezareh, Marjan
Pondarzewski, Malgorzata
Brown, Stephen J
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Published in Antiviral chemistry & chemotherapy. 2004, vol. 15, no. 4, p. 207-22
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.
Keywords AntigensCD4/metabolismCell LineDown-Regulation/drug effectsEndocytosis/drug effectsEnzyme Inhibitors/pharmacologyHumansIsoenzymes/antagonists & inhibitors/metabolismPhorbol Esters/pharmacologyProtein Kinase C/antagonists & inhibitors/metabolismProtein Transport/drug effectsReceptorsCCR5/metabolismReceptorsCXCR4/metabolismReceptorsHIV/metabolismT-Lymphocytes/drug effects/metabolismTetradecanoylphorbol Acetate/pharmacology
PMID: 15457682
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Research group Obésité et syndrome métabolique (803)
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HEZAREH, Marjan et al. Mechanisms of HIV receptor and co-receptor down-regulation by prostratin: role of conventional and novel PKC isoforms. In: Antiviral chemistry & chemotherapy, 2004, vol. 15, n° 4, p. 207-22. https://archive-ouverte.unige.ch/unige:90663

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Deposited on : 2016-12-21

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