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Inhibition of Orbivirus Replication by Fluvastatin and Identification of the Key Elements of the Mevalonate Pathway Involved

Mohd Jaafar, Fauziah; Monsion, Baptiste; Belhouchet, Mourad; Mertens, Peter P. C.; Attoui, Houssam

Inhibition of Orbivirus Replication by Fluvastatin and Identification of the Key Elements of the Mevalonate Pathway Involved Thumbnail


Authors

Fauziah Mohd Jaafar

Baptiste Monsion

Mourad Belhouchet

Houssam Attoui



Abstract

Statin derivatives can inhibit the replication of a range of viruses, including hepatitis C virus (HCV, Hepacivirus), dengue virus (Flavivirus), African swine fever virus (Asfarviridae) and poliovirus (Picornaviridae). 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(−/−) mice with fluvastatin promoted their survival upon challenge with live BTV, although only limited protection was observed.

Journal Article Type Article
Acceptance Date Jul 20, 2021
Online Publication Date Jul 23, 2021
Publication Date Aug 1, 2021
Deposit Date Jul 27, 2021
Publicly Available Date Jul 27, 2021
Journal Viruses
Electronic ISSN 1999-4915
Publisher MDPI AG
Peer Reviewed Peer Reviewed
Volume 13
Issue 8
Article Number 1437
DOI https://doi.org/10.3390/v13081437
Keywords Virology; Infectious Diseases
Public URL https://nottingham-repository.worktribe.com/output/5841656
Publisher URL https://www.mdpi.com/1999-4915/13/8/1437

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