title: Replication-attenuated Human Adenoviral Type 4 vectors elicit capsid dependent enhanced innate immune responses that are partially dependent upon interactions with the complement system.
abstract: Human Adenovirus Type 4 (HAdV-4) is responsible for epidemic outbreaks of Acute Respiratory Disease (especially in military recruits), and is known to cause significant morbidity with several reported cases of mortality. However, we do not understand why this serotype causes such high morbidity, and have little insight into the immunobiology of HAdV-4 infections. We have now developed a replication attenuated HAdV-4 vector system, and through it, demonstrate that HAdV-4 virions have enhanced infectivity of certain cell types and reveal aspects of the serotype-specific heightened innate immunogenicity of infectious HAdV-4 capsids both in vitro and in vivo. We further found that elements of this serotype-specific immunogenicity were dependent upon interactions with the complement system. These findings provide insights into the mechanisms possibly underlying the known morbidity accompanying wild-type HAdV-4 infections as well as highlight important considerations when considering development of alternative serotype vectors.
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Zachary C
authors.initials: ZC
authors.lastname: Hartman
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Appledorn
authors.forename: Delila
authors.initials: D
authors.lastname: Serra
authors.forename: Oliver
authors.initials: O
authors.lastname: Glass
authors.forename: Todd B
authors.initials: TB
authors.lastname: Mendelson
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Clay
authors.forename: Andrea
authors.initials: A
authors.lastname: Amalfitano
mesh_terms: D000260:Adenoviruses, Human / Q000145:classification / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D002213:Capsid / Q000276:immunology / Q000378:metabolism; D036022:Capsid Proteins / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D003165:Complement System Proteins / Q000378:metabolism*; D003713:Dendritic Cells / Q000821:virology; D004847:Epithelial Cells / Q000821:virology; D005822:Genetic Vectors; D006801:Humans; D007113:Immunity, Innate; D010957:Plasmids / Q000235:genetics; D012703:Serotyping; D014771:Virion / Q000378:metabolism; D014779:Virus Replication
chemical_list: D036022:Capsid Proteins; D003165:Complement System Proteins