Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Insect-Specific Flavivirus Replication in Mammalian Cells is Inhibited by Physiological Temperature and the Zinc-Finger Antiviral Protein

Version 1 : Received: 4 February 2021 / Approved: 8 February 2021 / Online: 8 February 2021 (15:46:14 CET)

A peer-reviewed article of this Preprint also exists.

Colmant, A.M.G.; Hobson-Peters, J.; Slijkerman, T.A.P.; Harrison, J.J.; Pijlman, G.P.; van Oers, M.M.; Simmonds, P.; Hall, R.A.; Fros, J.J. Insect-Specific Flavivirus Replication in Mammalian Cells Is Inhibited by Physiological Temperature and the Zinc-Finger Antiviral Protein. Viruses 2021, 13, 573. Colmant, A.M.G.; Hobson-Peters, J.; Slijkerman, T.A.P.; Harrison, J.J.; Pijlman, G.P.; van Oers, M.M.; Simmonds, P.; Hall, R.A.; Fros, J.J. Insect-Specific Flavivirus Replication in Mammalian Cells Is Inhibited by Physiological Temperature and the Zinc-Finger Antiviral Protein. Viruses 2021, 13, 573.

Journal reference: Viruses 2021, 13, 573
DOI: 10.3390/v13040573

Abstract

The genus Flavivirus contains pathogenic vertebrate-infecting flaviviruses (VIFs) and in-sect-specific flaviviruses (ISF). ISF transmission to vertebrates is inhibited at multiple stages of the cellular infection cycle, via yet to be elucidated specific antiviral responses. The Zinc-finger an-tiviral protein (ZAP) in vertebrate cells can bind CpG dinucleotides in viral RNA, limiting virus replication. Interestingly, the genomes of ISFs contain more CpG dinucleotides compared to VIFs. In this study, we investigated whether ZAP prevents two recently discovered lineage II ISFs, Binjari (BinJV) and Hidden Valley viruses (HVV) from replicating in vertebrate cells. BinJV protein and dsRNA replication intermediates were readily observed in human ZAP knockout cells when cultured at 34 ˚C. In ZAP expressing cells, inhibition of the interferon response via interferon response factors 3/7 did not improve BinJV protein expression, whereas treatment with kinase inhibitor C16, known to reduce ZAP’s antiviral function, did. Importantly, at 34 ˚C both BinJV and HVV successfully completed the infection cycle in human ZAP knockout cells evident from infectious progeny virus in the cell culture supernatant. Therefore, we identify vertebrate ZAP as an important barrier that protects vertebrate cells from ISF infection This provides new insights into flavivirus evolution and the mechanisms associated with host switching.

Subject Areas

Insect-specific flavivirus; CpG; Dinucleotides; Innate immunity; Zinc-finger antiviral protein

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