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The World Health Organization has recently raised its alert level of a possible influenza pandemic to Phase 3. There are currently only two existing classes of influenza antivirals, so resistance could occur easily. However, one of the most conserved pathways in the life cycle of the influenza virus, the nuclear import of its RNA genome, remains a promising pathway to understand more thoroughly and potentially disrupt. As part of its life cycle, the genome-containing viral ribonucleoprotein complexes (vRNPs) of influenza A must enter the cell nucleus of the host to replicate and transcribe new viral genes and proteins.

Using virion-derived influenza A viral vRNP complexes, we have recently found that both nuclear localization signal 1 (NLS1, residues 1-13) and nuclear localization signal 2 (NLS2, residues 198-216) on nucleoprotein (NP) are responsible for mediating the nuclear import of vRNP complexes in digitonin-permeabilized cells, with NLS1 being the principal mediator. We have further found that the structural basis for the more potent ability of NLS1 to mediate nuclear import is due to NLS1 being both more highly exposed on vRNPs, and exposed on a greater number of vRNPs compared to NLS2. To better understand the role of and degrees of exposure of the NLSs on vRNPs and newly-synthesized NP during the influenza A life cycle, we are currently investigating NLS exposure at various stages of the influenza A life cycle. These studies should prove useful in gaining a better understanding of how influenza A undergoes nuclear import and nuclear export during its life cycle, and pave the way for designing specific, new inhibitors against a highly-conserved pathway of the influenza A viral life cycle.