Abstract
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.
Highlights
The most redoubtable obstacle to the eradication of HIV is the persistence of latent virus in infected patients under antiretroviral therapy (ART)
To evaluate whether ingenol synthetic derivatives (ISD) were able to activate the HIV LTR, the three compounds were tested in five J-Lat cell lines
We introduce three novel semi-synthetic protein kinase C (PKC) activators derived from ingenol diterpenes isolated from Euphorbia tirucalli
Summary
The most redoubtable obstacle to the eradication of HIV is the persistence of latent virus in infected patients under antiretroviral therapy (ART). Active antiretroviral therapy (HAART) targets only actively replicating virus and it has little influence on latent viral reservoirs. The focus of most therapeutic strategies has been on eliminating this HIV reservoir to diminish the number of latently infected cells and to achieve a functional or even a sterilizing cure. A potentially useful strategy, sometimes termed ‘‘shock and kill’’ [6,7], aims to attack the latent reservoir by treating patients with HIV-activating agents to stimulate viral replication in latently infected cells while blocking de novo infection with antiretroviral therapy. An ideal drug to induce HIV-LTR should be potent, orally available, nontoxic, active in a wide variety of latently infected cell types, and capable of penetrating tissues, including the central nervous system [8]
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