Interference with the production of infectious viral particles and bimodal inhibition of replication are broadly conserved antiviral properties of IFITMs

Kevin Tartour (1) , Xuan-Nhi Nguyen (1) , Romain Appourchaux (1) , Sonia Assil (2) , Véronique Barateau (1) , Louis-Marie Bloyet (3) , Julien Burlaud Gaillard (4) , Marie Confort (5) , Beatriz Escudero-Perez (6) , Henri Gruffat (7) , Saw See Hong (5) , Marie Moroso (8) , Olivier Reynard (6) , Stéphanie Reynard (9) , Elodie Decembre (2) , Najate Ftaich (5) , Axel Rossi (10) , Nannan Wu (1) , Frederick Arnaud (5) , Sylvain Baize (9, 11) , Marlène Dreux (2) , Denis Gerlier (3) , Gláucia Paranhos-Baccalà (8) , Viktor Volchkov (6) , Philippe Roingeard (4, 12) , Andrea Cimarelli (1)

1 LP2L - Interaction hôte pathogène lors de l'infection lentivirale – Host-Pathogen Interaction during Lentiviral Infection
2 Trafic Vésiculaire, Réponse Innée et Virus – Vesicular trafficking, Innate response
3 IbIV - Immunobiologie des infections virales – Immunobiology of Viral Infections
4 UNIV Tours - Plateforme IBISA de Microscopie Electronique [CHRU de Tours]
5 IVPC - Infections Virales et Pathologie Comparée - UMR 754
6 BMPV - Bases moléculaires de la pathogénicité virale – Molecular Basis of Viral Pathogenicity
7 Herpesvirus oncogènes – Oncogenic Herpesviruses
8 LPE-Fondation Mérieux - Laboratoire des pathogènes émergents -- Emerging Pathogens Laboratory
9 UBIVE - Biologie des Infections Virales Émergentes - Biology of Emerging Viral Infections
10 NUCLEOVIR
11 Institut Pasteur de Lyon
12 Centre national de référence du VIH INSERM U966

IFITMs are broad antiviral factors that block incoming virions in endosomal vesicles, protecting target cells from infection. In the case of HIV-1, we and others reported the existence of an additional antiviral mechanism through which IFITMs lead to the production of virions of reduced infectivity. However, whether this second mechanism of inhibition is unique to HIV or extends to other viruses is currently unknown. To address this question, we have analyzed the susceptibility of a broad spectrum of viruses to the negative imprinting of the virion particles infectivity by IFITMs. The results we have gathered indicate that this second antiviral property of IFITMs extends well beyond HIV and we were able to identify viruses susceptible to the three IFITMs altogether (HIV-1, SIV, MLV, MPMV, VSV, MeV, EBOV, WNV), as well as viruses that displayed a member-specific susceptibility (EBV, DUGV), or were resistant to all IFITMs (HCV, RVFV, MOPV, AAV). The swapping of genetic elements between resistant and susceptible viruses allowed us to point to specificities in the viral mode of assembly, rather than glycoproteins as dominant factors of susceptibility. However, we also show that, contrarily to X4-, R5-tropic HIV-1 envelopes confer resistance against IFITM3, suggesting that viral receptors add an additional layer of complexity in the IFITMs-HIV interplay. Lastly, we show that the overall antiviral effects ascribed to IFITMs during spreading infections, are the result of a bimodal inhibition in which IFITMs act both by protecting target cells from incoming viruses and in driving the production of virions of reduced infectivity. Overall, our study reports for the first time that the negative imprinting of the virion particles infectivity is a conserved antiviral property of IFITMs and establishes IFITMs as a paradigm of restriction factor capable of interfering with two distinct phases of a virus life cycle.

Domains: Life Sciences [q-bio]

Kevin Tartour, Xuan-Nhi Nguyen, Romain Appourchaux, Sonia Assil, Véronique Barateau, et al.. Interference with the production of infectious viral particles and bimodal inhibition of replication are broadly conserved antiviral properties of IFITMs. PLoS Pathogens, 2017, 13 (9), pp.e1006610. ⟨10.1371/journal.ppat.1006610⟩. ⟨hal-01774659⟩