Dual role of novel ingenol derivatives from Euphorbia tirucalli in HIV replication: inhibition of de novo infection and activation of viral LTR.
HIV infection is not cleared by antiretroviral drugs due to the presence of latently infected cells that are not eliminated with current therapies and persist in the blood and organs of infected patients. New compounds to activate these latent reservoirs have been evaluated so that, along with HAART, they can be used to activate latent virus and eliminate the latently infected cells resulting in eradication of viral infection. Here we describe three novel diterpenes isolated from the sap of Euphorbia tirucalli, a tropical shrub. These molecules, identified as ingenols, were modified at carbon 3 and termed ingenol synthetic derivatives (ISD). They activated the HIV-LTR in reporter cell lines and human PBMCs with latent virus in concentrations as low as 10 nM. ISDs were also able to inhibit the replication of HIV-1 subtype B and C in MT-4 cells and human PBMCs at concentrations of EC50 0.02 and 0.09 µM respectively, which are comparable to the EC50 of some antiretroviral currently used in AIDS treatment. Control of viral replication may be caused by downregulation of surface CD4, CCR5 and CXCR4 observed after ISD treatment in vitro. These compounds appear to be less cytotoxic than other diterpenes such as PMA and prostratin, with effective dose versus toxic dose TI>400. Although the mechanisms of action of the three ISDs are primarily attributed to the PKC pathway, downregulation of surface receptors and stimulation of the viral LTR might be differentially modulated by different PKC isoforms.
Departamento de Genética, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
Celina M
CM
Abreu
Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
Sarah L
SL
Price
Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
Erin N
EN
Shirk
Departamento de Genética, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
Rodrigo D
RD
Cunha
Kyolab, Campinas, Brazil.
Luiz F
LF
Pianowski
Departamento de Genética, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
Janice E
JE
Clements
Departamento de Genética, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
Amilcar
A
Tanuri
Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
Lucio
L
Gama
D019380:Anti-HIV Agents / Q000494:pharmacology*; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods; D015704:CD4 Antigens / Q000378:metabolism; D002460:Cell Line; D004224:Diterpenes / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D028481:Euphorbia / Q000378:metabolism*; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D006679:HIV Seropositivity / Q000188:drug therapy / Q000378:metabolism / Q000821:virology; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000821:virology; D019713:Receptors, CCR5 / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D017735:Virus Latency / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects*
D019380:Anti-HIV Agents; C584933:CCR5 protein, human; D015704:CD4 Antigens; C527276:CXCR4 protein, human; D004224:Diterpenes; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; C008125:ingenol