The Botanical Glycoside Oleandrin Inhibits Human T-cell Leukemia Virus Type-1 Infectivity and Env-Dependent Virological Synapse Formation

Abstract

At present, there are no antiretroviral drugs that inhibit incorporation of the envelope glycoprotein into newly-synthesized virus particles. The botanical glycoside, oleandrin, derived from extracts of Nerium oleander, has previously been shown to reduce the levels of the gp120 envelope glycoprotein on human immunodeficiency virus type-1 (HIV-1) particles and inhibit HIV-1 infectivity in vitro. We therefore tested whether oleandrin or an extract from N. oleander could also inhibit the infectivity of the human T-cell leukemia virus type-1 (HTLV-1): A related enveloped retrovirus and emerging tropical infectious agent. The treatment of HTLV-1+ lymphoma T-cells with either oleandrin or a N. oleander extract did not significantly inhibit viral replication or the release of p19Gag-containing particles into the culture supernatants. However, the collected virus particles from treated cells exhibited reduced infectivity on primary human peripheral blood mononuclear cells (huPBMCs). Unlike HIV-1, extracellular HTLV-1 particles are poorly infectious and viral transmission typically occurs via direct intercellular interactions across a virological synapse. We therefore investigated whether oleandrin or a N. oleander extract could inhibit virus transmission from a GFP-expressing HTLV-1+ lymphoma T-cell-line to huPBMCs in co-culture assays. These results demonstrated that both oleandrin and the crude phytoextract inhibited the formation of virological synapses and the transmission of HTLV-1 in vitro. Importantly, these findings suggest oleandrin may have broad antiviral activity against enveloped viruses by reducing the incorporation of the envelope glycoprotein into mature particles, a stage of the infection cycle not targeted by modern HAART.

Prophylactic and Therapeutic Inhibition of In Vitro SARS-CoV-2 Replication by Oleandrin

“…We also reported that oleandrin treatment of cells infected with HTLV-1 resulted in reduced infectivity of progeny virus particles. Oleandrin inhibited virological synapse formation and consequent transmission of HTLV-1 in vitro (18). Collectively this research strongly suggested that oleandrin and defined plant extracts with this molecule have a strong potential against enveloped viruses.…”

“…A recent review described antiviral activities of cardiac glycosides against cytomegalovirus, Herpes simplex virus, adenovirus, chikungunya virus, coronaviruses, respiratory syncytial virus, Ebola virus, influenza virus and human immunodeficiency virus (16). We recently reported that oleandrin, a unique lipid-soluble cardiac glycoside obtained solely from Nerium oleander, has strong antiviral activity against HIV-1 and HTLV-1 (17,18). Importantly, in studies with HIV-1, a unique antiviral activity of oleandrin was observed in terms of producing viral progeny with a greatly diminished potential to infect new target cells (17).…”

Cytotoxicity of Oleandrin Is Mediated by Calcium Influx and by Increased Manganese Uptake in Saccharomyces cerevisiae Cells

“…Apart from being a cardiac glycoside, oleandrin has been gathering attention due to its anti-tumoral [ 12 , 13 , 14 , 15 , 16 ] and antiviral potential [ 8 , 17 , 18 , 19 ], but its pharmacological use is held back by its variable toxicity. In this study, using the model S. cerevisiae , we detected oleandrin-induced fluctuations in cell Ca 2+ , which could be related to the Ca 2+ entry via the Cch1/Mid1 plasma membrane channel ( Figure 5 ).…”

<p>Antiviral Effects of Oleandrin</p>

“…These data further confirmed the Anti-HTLV-1 p19-Gag ELISA results from previous co-culture experiments and demonstrated that oleandrin and the N. oleander phytoextract inhibited HTLV-1 infectivity and Env-dependent VSformation. 19 As others have reported that oleandrin can readily cross the blood-brain barrier and penetrate the CNS in mouse xenograft models of malignant glioma and exhibited neuroprotective effects in vivo models of ischemic stroke,- 7,57,58 this molecule could potentially be used to inhibit HTLV-1 replication and viral gene expression in the CNS and may have therapeutic implications for the treatment of…”

“…Because of the recent SARS-CoV-2 (COVID-19) worldwide pandemic, attention has been drawn to the antiviral effects of cardiac glycosides and oleandrin as extracts containing this molecule may represent 're-purposing' of a novel molecule. Published reports from in vitro cell culture studies have shown that oleandrin and extracts containing this molecule are effective against HIV, Ebola virus as well as the HTLV-1 and other viruses important to human health and wellbeing; [16][17][18][19] however, it is the unique antiviral mechanisms of oleandrin that merits additional attention. The ability of oleandrin to inhibit the relative infectivity of progeny virus particles may offer a unique approach to treating certain viral diseases.…”