Figure 7. Model depicting the evolutionary bottleneck for avian influenza viruses encountering the host restriction factor MxA.

To establish a new lineage in the human population, avian influenza A viruses have to acquire several adaptive mutations in almost all viral proteins, including MxA escape mutations in NP. However, the acquisition of MxA escape amino acids in NP is associated with severely reduced viral fitness, due to impaired nuclear import of vRNPs. Stabilizing mutations in NP (e.g. 16D) are required to overcome this fitness restriction, but are not sufficient to restore viral growth properties. As a consequence further additional mutations in NP and probably other viral gene products are required.