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Dual role of novel ingenol derivatives from Euphorbia tirucalli in HIV replication: inhibition of de novo infection and activation of viral LTR.

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.

SUBMITTER: Abreu CM

PROVIDER: S-EPMC4020785 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Dual role of novel ingenol derivatives from Euphorbia tirucalli in HIV replication: inhibition of de novo infection and activation of viral LTR.

Abreu Celina M CM Price Sarah L SL Shirk Erin N EN Cunha Rodrigo D RD Pianowski Luiz F LF Clements Janice E JE Tanuri Amilcar A Gama Lucio L

PloS one 20140514 5

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 Euph ...[more]

PMID: 24827152

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Project description:BackgroundLTR retrotransposons are a class of mobile genetic elements containing two similar long terminal repeats (LTRs). Currently, LTR retrotransposons are annotated in eukaryotic genomes mainly through the conventional homology searching approach. Hence, it is limited to annotating known elements.ResultsIn this paper, we report a de novo computational method that can identify new LTR retrotransposons without relying on a library of known elements. Specifically, our method identifies intact LTR retrotransposons by using an approximate string matching technique and protein domain analysis. In addition, it identifies partially deleted or solo LTRs using profile Hidden Markov Models (pHMMs). As a result, this method can de novo identify all types of LTR retrotransposons. We tested this method on the two pairs of eukaryotic genomes, C. elegans vs. C. briggsae and D. melanogaster vs. D. pseudoobscura. LTR retrotransposons in C. elegans and D. melanogaster have been intensively studied using conventional annotation methods. Comparing with previous work, we identified new intact LTR retroelements and new putative families, which may imply that there may still be new retroelements that are left to be discovered even in well-studied organisms. To assess the sensitivity and accuracy of our method, we compared our results with a previously published method, LTR_STRUC, which predominantly identifies full-length LTR retrotransposons. In summary, both methods identified comparable number of intact LTR retroelements. But our method can identify nearly all known elements in C. elegans, while LTR_STRUCT missed about 1/3 of them. Our method also identified more known LTR retroelements than LTR_STRUCT in the D. melanogaster genome. We also identified some LTR retroelements in the other two genomes, C. briggsae and D. pseudoobscura, which have not been completely finished. In contrast, the conventional method failed to identify those elements. Finally, the phylogenetic and chromosomal distributions of the identified elements are discussed.ConclusionWe report a novel method for de novo identification of LTR retrotransposons in eukaryotic genomes with favorable performance over the existing methods.

Dataset Information

Dual role of novel ingenol derivatives from Euphorbia tirucalli in HIV replication: inhibition of de novo infection and activation of viral LTR.

Publications

Dual role of novel ingenol derivatives from Euphorbia tirucalli in HIV replication: inhibition of de novo infection and activation of viral LTR.

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