ID: 153: Block in nuclear vRNP import prevents highly pathogenic avian influenza A viruses from gaining MxA resistance
To cross the species barrier and establish a new lineage in humans avian influenza A viruses (FLUAV) have to overcome innate immune responses of the host. The IFN-induced large dynamin-like GTPase MxA is a key component in antiviral defense against FLUAV. Human-adapted FLUAV carry an amino acid motive in their nucleoprotein that confers MxA-resistance. This motive derived from the pandemic 1918 virus consists of three amino acids (100V, 283P, 313Y) and is highly conserved in human circulating strains but is absent in all known avian strains. Moreover, this motive never emerged in patients infected with highly pathogenic H5N1 viruses. The latter finding suggests that MxA-resistance might be difficult to achieve for H5N1 viruses. We can now show that human-derived H5N1 viruses, artificially harboring the three MxA-resistance conferring amino acids in their NPs exhibit impaired viral growth. This can be observed in all cell culture systems tested, including cell lines of mammalian and avian origin. Dissecting individual steps in the viral life cycle revealed that this is due to diminished nuclear import of incoming vRNPs. This recombinant virus is genetically instable and acquired single compensatory mutations in NP (D51N, G16D, D101Y, Y385C). With exception of G16D, these compensatory mutations abrogated MxA-resistance. However, these compensatory mutations are not able to completely restore efficient nuclear vRNP import and thus viral fitness. We therefore speculate that gaining MxA-resistance is at the expense of viral fitness – a hurdle that might be too high for H5N1 viruses to establish a new lineage in the human population.