Influenza A Virus Strains Differ in Sensitivity to the Antiviral Action of Mx-GTPase

Abstract

Interferon-mediated host responses are of great importance for controlling influenza A virus infections. It is well established that the interferon-induced Mx proteins possess powerful antiviral activities toward most influenza viruses. Here we analyzed a range of influenza A virus strains for their sensitivities to murine Mx1 and human MxA proteins and found remarkable differences. Virus strains of avian origin were highly sensitive to Mx1, whereas strains of human origin showed much weaker responses. Artificial reassortments of the viral components in a minireplicon system identified the viral nucleoprotein as the main target structure of Mx1. Interestingly, the recently reconstructed 1918 H1N1 "Spanish flu" virus was much less sensitive than the highly pathogenic avian H5N1 strain A/Vietnam/1203/04 when tested in a minireplicon system. Importantly, the human 1918 virus-based minireplicon system was almost insensitive to inhibition by human MxA, whereas the avian influenza A virus H5N1-derived system was well controlled by MxA. These findings suggest that Mx proteins provide a formidable hurdle that hinders influenza A viruses of avian origin from crossing the species barrier to humans. They further imply that the observed insensitivity of the 1918 virus-based replicon to the antiviral activity of human MxA is a hitherto unrecognized characteristic of the "Spanish flu" virus that may contribute to the high virulence of this unusual pandemic strain.

Effects of allelic variations in the human myxovirus resistance protein A on its antiviral activity

“…G interface variants affect antiviral activity and GTP hydrolysis-To test the effect of the variations in the G domain on the function of MxA, we initially determined the capacity of these variants to inhibit polymerase activity of a highly pathogenic H5N1 FLUAV (30) using a previously described minireplicon reporter assay (31). Viral ribonucleoprotein complexes (vRNPs) were reconstituted by co-expressing the viral polymerase subunits, viral NP and an artificial RNA minigenome encoding a firefly luciferase reporter gene.…”

“…We generated five artificial mutants replacing V470 with non-polar amino acids of increasing size (alanine, leucine and phenylalanine), with the negatively charged amino acid aspartate or with the polar amino acid asparagine. The effects of the mutants on MxA antiviral activity were tested in the minireplicon reporter system of FLUAV (31). The enhancement of antiviral activity induced by glycine at position 470 (Fig.…”

Structural basis of oligomerization in the stalk region of dynamin-like MxA

“…Next, inhibition of the polymerase complex of a highly pathogenic H5N1 influenza virus (isolated from a fatal human case in Vietnam 27 ) was assessed in a mini-replicon reporter assay 28 . As previously shown, wt MxA inhibited viral replication by 80% (Fig.…”

An engineered avian-origin influenza A virus for pancreatic ductal adenocarcinoma virotherapy

“…Indeed, no recombinant IAV of any origin has been appraised so far for PDA treatment, and the relative small number of previous investigations concerning the use of IAV for virotherapy were focused on the human strain H1N1 A/Puerto Rico/8/34 (Bergmann et al, 2001;Muster et al, 2004;Sturlan et al, 2010;Wolschek et al, 2011). Importantly, the choice of a particular viral isolate is likely to affect its efficacy as an OV because IAVs differ in their ability to counteract host IFN response (Geiss et al, 2002;Hayman et al, 2006;Kochs et al, 2007), induce apoptosis (Kasloff et al, 2014) and in their sensitivity to host ISGs (Dittmann et al, 2008).…”

“…RIG-I and MAVS) were expressed and further induced after virus infection in both cell lines, others, such as IFN-a, IFN-b and MxA, were constitutively expressed at low levels and then induced upon infection only in HPDE6 cells. Conversely to many human IAVs, which are able to cope with Mx gene product, thanks to mutation within specific recognition sites on the NP protein, in general, avian IAVs are more sensitive to MxA activity and in order to be stably introduced in mammals often they have to acquire adaptive mutations to escape this restriction factor (Dittmann et al, 2008;Manz et al, 2013;Zimmermann et al, 2011). Because the H7N3 NP protein displays a typical avian signature (Riegger et al, 2015), it is possible that the expression of IFNstimulated genes (ISGs), such as MxA, together with IFN, might account for the low growth rate and ensuing oncolytic activity (Kasloff et al, 2014) displayed by the wild-type H7N3 virus in HPDE6 cells.…”