Differential effects of phorbol-13-monoesters on human immunodeficiency virus reactivation.
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.
Márquez
Nieves
N
Departamento de Biología Celular, Fisiología e Inmunología, Facultad de Medicina, Avda. de Menendez Pidal s/n, 14004 Universidad de Córdoba, Spain.
Calzado
Marco A
MA
Sánchez-Duffhues
Gonzalo
G
Pérez
Moisés
M
Minassi
Alberto
A
Pagani
Alberto
A
Appendino
Giovanni
G
Diaz
Laura
L
Muñoz-Fernández
Maria Angeles
MA
Muñoz
Eduardo
E
D000328:Adult; D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology*; D015703:Antigens, CD / Q000378:metabolism; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D019169:Jurkat Cells; D007963:Leukocytes, Mononuclear / Q000166:cytology; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism; D010703:Phorbol Esters / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D014775:Virus Activation / Q000187:drug effects*; D017735:Virus Latency / Q000187:drug effects*
D019380:Anti-HIV Agents; D015703:Antigens, CD; D016328:NF-kappa B; D010703:Phorbol Esters; D051550:I-kappa B Kinase; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases; D048670:MAP Kinase Kinase 4