Abstract
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.
Highlights
The interferon-induced transmembrane proteins (IFITMs) are a family of highly related proteins that present two transmembrane domains (TM) connected by a short linker region and an N and C-termini of variable length [1, 2]
More recently in the case of HIV-1, ours and other laboratories have highlighted the existence of an additional antiviral mechanism with which IFITMs could act in virus-producing cells, leading to the production of virion particles of reduced infectivity
We show that HIV-1 strains that engage the CCR5 co-receptor display a notable resistance towards IFITM3, indicating that at least in the case of HIV-1, coreceptor usage is likely to add an additional layer of complexity in the relationship established between IFITMs and the virus, that may or may not extend to other viral families as well
Summary
The interferon-induced transmembrane proteins (IFITMs) are a family of highly related proteins that present two transmembrane domains (TM) connected by a short linker region and an N and C-termini of variable length [1, 2] In humans, this family is composed of five expressed members: IFITM1, 2 and 3 that are bona fide interferon-regulated genes [3], IFITM5 mainly expressed in bone tissue and genetically linked to Osteogenesis Imperfecta [4, 5], and IFITM10 that remains poorly characterized. The exact molecular mechanism by which IFITMs modify the biophysical properties of membranes remains unclear, having been controversially linked in the past to changes in membrane cholesterol levels [44, 45], or more recently to interactions with other cellular co-factors [46]
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