Early Steps of Clathrin-Mediated Endocytosis Involved in Phagosomal Escape of Fcγ Receptor-Targeted Adenovirus

Neutralized Adenovirus-Immune Complexes Can Mediate Effective Gene Transfer via an Fc Receptor-Dependent Infection Pathway

“…Evaluation of gene transfer was performed as described in the legend to Ad away from native target cells (CAR-expressing epithelial cells) toward a new target cell (Fc␥R-bearing antigen-presenting cells). This report is also distinct from studies in which nonneutralizing antibodies have been used to retarget Ad to Fc␥R-bearing cells (14,44,45), since modification of tropism was observed following treatment with whole, unfractionated neutralizing serum rather than selected monoclonal antibodies. Finally, this study is distinct from studies in which human sera have been analyzed to determine the relative contribution of neutralizing antibodies against each of the major capsid proteins (12,52,55,59,60,67,68,73,75,79) since those studies examined the effects of subsets of antibodies rather than whole, unfractionated neutralizing serum on the infectivity of Ad.…”

“…The lowaffinity receptors (Fc␥RII and Fc␥RIII) clear immune complexes from tissue and serum and enhance the immune response to foreign antigens contained in the antibody-antigen complex (30). In the event that viable viral capsids gain entry to an antigen-presenting cell via Fc receptor interaction, there exists a potential viral gene expression with the antigen-presenting cell (14,44), a mechanism that can lead to particularly strong immune responses to virus-encoded antigens.…”

Endosomophagy clears disrupted early endosomes but not virus particles during virus entry into cells     

“…Invariably, host defense against the pathogens or host cell damage antagonizes the intruders [5] [6] [7]. Damage to host cells occurs during invasion of bacteria and non-enveloped viruses, including Salmonella, Shigella, Listeria or Adenovirus, which disrupt phagocytic vacuoles and endosomes [8] [9]. Disrupted vacuoles recruit beta-galactoside binding lectins, such as galectin-3 (Gal3) and Gal8, both widely expressed in epithelial cells [10] [11] [12] [13].…”

Adenovirus-triggered innate signalling pathways

“…Indeed, macrophage receptors, such as Fc receptor and DC-Sign have been shown to facilitate cellular binding requiring anti Ad antibodies and lactoferrin, respectively [67][68][69]. If modified by an Fc fusion protein, they can directly attach to the high affinity FcR CD64 [70]. In immature myeloid dendritic cells, adenoviruses escape from the phagolysosome and this requires the virion protease similarly to what was found in non-immune cells [71]; however, much less is known about additional steps of Ad entry into mononuclear phagocytes compared to other non-immune cells.…”