Adenovirus Tales: From the Cell Surface to the Nuclear Pore Complex

Despite lingering safety concerns [1] and potential restrictions imposed by the host immune response, including the innate immune pattern recognition receptors (PRR), replicationdefective and conditionally replicating human and nonhuman adenovirus (AdV) vectors continue to be a favorite vehicle for short-term (e.g., vaccine) and long-term gene delivery. This is due in part to several desirable features of AdV including their broad tissue tropism, their ample capacity for foreign gene insertion, and their LEGO-like structural adaptability (Fig 1A) to add, delete, and swap proteins and motifs from other viruses or host molecules. While much is known about the molecular genetics and replication of AdVs, many investigators are continuing to decipher the captivating intracellular events of the first thirty minutes in the virus life cycle. This Pearl accentuates the strikingly diverse mechanisms for AdV entry, comparing human AdV type 5 (HAdV-C5) in epithelial cells and canine type 2 (CAdV2, or commonly referred to as CAV-2) in neurons. Similar viral and cellular proteins are used, and although the function of the cellular protein varies among cell types, these cell protein—virus associations promote similar outcomes. We also highlight some outstanding questions and hurdles needed to improve vector-mediated gene and vaccine delivery and treatments for AdV disease. The take home message is that one may be able to take advantage of a better understanding of these cell entry variations to control AdV pathogenesis and vector tropism for gene therapy.