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Biochem Pharmacol. 2009 Mar 15;77(6):965-78. doi: 10.1016/j.bcp.2008.11.025. Epub 2008 Dec 3.

SJ23B, a jatrophane diterpene activates classical PKCs and displays strong activity against HIV in vitro.

Author information

1
Unidad de Inmunopatología del SIDA, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Ctra. Majadahonda-Pozuelo, km. 2, 28220 Majadahonda, Madrid, Spain.

Abstract

Existence of virus reservoirs makes the eradication of HIV infection extremely difficult. Current drug therapies neither eliminate these viral reservoirs nor prevent their formation. Consequently, new strategies are needed to target these reservoirs with the aim of decreasing their size. We analysed a series of jatrophane diterpenes isolated from Euphorbia hyberna and we found that one of them, SJ23B, induces the internalization of the HIV-1 receptors CD4, CXCR4 and CCR5 and prevents R5 and X4 viral infection in human primary T cells at the nanomolar range. Moreover, SJ23B is a potent antagonist of HIV-1 latency. Using Jurkat-LAT-GFP cells, a model for HIV-1 latency, we found that prostratin and SJ23B activate HIV-1 gene expression, with SJ23B being at least 10-fold more potent than prostratin. SJ23B did not elicit transforming foci activity in NIH 3T3 cells but is a potent activator of PKCalpha and delta as measured by in vitro kinase assays and by cellular translocation experiments. By using isoform-specific PKC inhibitors we found that cPKCs are critical for SJ23B-induced HIV-1 reactivation. We also showed that both SJ23B-induced IkappaBalpha degradation and NF-kappaB activation were inhibited by the classical PKC inhibitor, Gö6976. Accordingly, SJ23B synergizes with ionomycin to translocate PKCalpha to the plasma membrane and to activate the NF-kappaB pathway. Moreover, SJ23B activates both NF-kappaB and Sp1-dependent transcriptional activities in primary T cells. We have shown that diterpene jatrophanes represent a new member of anti-AIDS agents that could be developed for mitigating HIV reactivation.

PMID:
19100719
DOI:
10.1016/j.bcp.2008.11.025
[Indexed for MEDLINE]

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