| Summary: | Statin derivatives can inhibit the replication of a range of viruses, including hepatitis C virus (HCV, <i>Hepacivirus</i>), dengue virus (<i>Flavivirus</i>), African swine fever virus (<i>Asfarviridae</i>) and poliovirus (<i>Picornaviridae</i>). We assess the antiviral effect of fluvastatin in cells infected with orbiviruses (bluetongue virus (BTV) and Great Island virus (GIV)). The synthesis of orbivirus outer-capsid protein VP2 (detected by confocal immunofluorescence imaging) was used to assess levels of virus replication, showing a reduction in fluvastatin-treated cells. A reduction in virus titres of ~1.7 log (98%) in fluvastatin-treated cells was detected by a plaque assay. We have previously identified a fourth non-structural protein (NS4) of BTV and GIV, showing that it interacts with lipid droplets in infected cells. Fluvastatin, which inhibits 3-hydroxy 3-methyl glutaryl CoA reductase in the mevalonic acid pathway, disrupts these NS4 interactions. These findings highlight the role of the lipid pathways in orbivirus replication and suggest a greater role for the membrane-enveloped orbivirus particles than previously recognised. Chemical intermediates of the mevalonic acid pathway were used to assess their potential to rescue orbivirus replication. Pre-treatment of IFNAR<sup>(−/−)</sup> mice with fluvastatin promoted their survival upon challenge with live BTV, although only limited protection was observed.
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