Differential effects of phorbol-13-monoesters on human immunodeficiency virus reactivation.

Abstract

The persistence of latent reservoirs of HIV-1 represents a major barrier to virus eradication in patients treated with antiretrovirals. Prostratin is a non-tumor promoting 12-deoxyphorbol monoester capable of up-regulating viral expression from latent provirus and therefore is potentially useful for HIV adjuvant therapy and similar properties might be elicited by related non-tumor promoting phorboids. We have therefore investigated a series of phorbol 13-monoesters for their capacity to reactivate HIV latency. Using a Jurkat T cell line containing latent HIV proviruses, we found that prostratin and phorbol-13-stearate effectively activate HIV-1 gene expression in these latently infected cells, with phorbol-13-stearate being at least 10-fold more potent than prostratin, and its activity rapidly decreasing with a shortening of the acyl side chain. We further demonstrated that phorbol-13-stearate and prostratin stimulate IKK-dependent phosphorylation and degradation of IkappaBalpha, leading to activation of NF-kappaB. Moreover, prostratin, phorbol-13-hexanoate and phorbol-13-stearate also activate the JNK and ERK pathways. Studies with isoform-specific PKC inhibitors suggest that the classical PKCs play a prominent role in the responses elicited by phorbol-13-stearate. Nevertheless, this compound induces a translocation pattern of the PKC isotypes alpha and delta to cellular compartments distinctly different from that elicited by prostratin and PMA.

• Authors: Nieves Márquez, Marco A Calzado, Gonzalo Sánchez-Duffhues, Moisés Pérez, Alberto Minassi, Alberto Pagani, Giovanni Appendino, Laura Diaz, Maria Angeles Muñoz-Fernández, Eduardo Muñoz
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 75 Issue 6 Pg. 1370-80 (Mar 15 2008) ISSN: 1873-2968 [Electronic] England
• PMID: 18241838 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-HIV Agents
• Antigens, CD
• NF-kappa B
• Phorbol Esters
• I-kappa B Kinase
• Protein Kinase C
• Extracellular Signal-Regulated MAP Kinases
• MAP Kinase Kinase 4

Topics

• Adult
• Animals
• Anti-HIV Agents (pharmacology)
• Antigens, CD (metabolism)
• CHO Cells
• Cells, Cultured
• Cricetinae
• Cricetulus
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• HIV-1 (drug effects, physiology)
• Humans
• I-kappa B Kinase (metabolism)
• Jurkat Cells
• Leukocytes, Mononuclear (cytology)
• MAP Kinase Kinase 4 (metabolism)
• MAP Kinase Signaling System (drug effects)
• NF-kappa B (metabolism)
• Phorbol Esters (pharmacology)
• Protein Kinase C (metabolism)
• T-Lymphocytes (drug effects, metabolism)
• Virus Activation (drug effects)
• Virus Latency (drug effects)