Many viruses deliver their genomes into the host cell’s nucleus before they replicate. While onco-retroviruses and papillomaviruses tether their genomes to host chromatin upon mitotic breakdown of the nuclear envelope, lentiviruses, such as human immunodeficiency virus, adenoviruses, herpesviruses, parvoviruses, influenza viruses, hepatitis B virus, polyomaviruses, and baculoviruses deliver their genomes into the nucleus of post-mitotic cells. This poses the significant challenge of slipping a DNA or RNA genome past the nuclear pore complex (NPC) embedded in the nuclear envelope. Quantitative fluorescence imaging is shedding new light on this process, with recent data implicating misdelivery of viral genomes at nuclear pores as a bottleneck to virus replication. Here, we infer NPC functions for nuclear import of viral genomes from cell biology experiments and explore potential causes of misdelivery, including improper virus docking at NPCs, incomplete translocation, virus-induced stress and innate immunity reactions. We conclude by discussing consequences of viral genome misdelivery for viruses and host cells, and lay out future questions to enhance our understanding of this phenomenon. Further studies into viral genome misdelivery may reveal unexpected aspects about NPC structure and function, as well as aid in developing strategies for controlling viral infections to improve human health.
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