Abstract
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.
Highlights
Viruses are highly efficient gene delivery devices when compared to alternative approaches such as naked nucleic acid delivery or artificial vectors, such as polyamine or liposome complexes [1,2,3]
Viruses that replicate in the intact cell nucleus must transport their genomes through the nuclear pore complex (NPC) embedded in the nuclear envelope [17,18,19,20,21,22,23,24]
It was demonstrated for human adenovirus (HAdV) that a significant fraction of incoming viral genomes do not make it into the nuclear compartment for replication upon virus docking and uncoating at the NPC
Summary
Viruses are highly efficient gene delivery devices when compared to alternative approaches such as naked nucleic acid delivery or artificial vectors, such as polyamine or liposome complexes [1,2,3]. In the case of DNA viruses and lentiviruses, immunity is frequently directed against the viral DNA (vDNA) in endosomes, the cytosol, and the nucleus [12,13,14,15,16] This can give rise to inflammasome or interferon activation, which is capable of restricting both the infection and transduction efficacy of viral vectors. Onco-retroviruses and papillomaviruses wait for the nuclear envelope to break down in mitosis, whereafter they tether to host chromatin and are planted in the reforming nucleus at telophase In both cases, nuclear access requires that the viral genome be freed from the enclosing capsid. The separation of the viral genome from the capsid is termed uncoating This critical reaction exposes the genetic information and is key to making progeny virions. This may be a basis for host defense mechanisms that evoke an intrinsic antiviral response
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