title: Ad5:Ad48 hexon hypervariable region substitutions lead to toxicity and increased inflammatory responses following intravenous delivery.
abstract: The development of adenoviral vectors for intravascular (i.v.) delivery will require improvements to their in vivo safety and efficacy. The hypervariable regions (HVRs) of the Ad5 hexon are a target for neutralizing antibodies, but also interact with factor X (FX), facilitating hepatocyte transduction. Ad48, a species D adenovirus, does not bind FX and has low seroprevalence. Therefore, it has been suggested that Ad5HVR48(1-7), a hexon-chimeric vector featuring the seven HVRs from Ad48, should display advantageous properties for gene therapy, by evading pre-existing Ad5 immunity and blocking FX interactions. We investigated the in vivo biodistribution of Ad5, Ad5HVR48(1-7), and Ad48 following i.v. delivery. Ad5HVR48(1-7) displayed reduced hepatocyte transduction and accumulation in Kupffer cells (KCs), but triggered a robust proinflammatory response, even at relatively low doses of vector. We detected elevated serum transaminases (48 hours) and increased numbers of periportal CD11b(+)/Gr-1(+) cells in the livers of Ad5HVR48(1-7)-treated animals following i.v., but not intramuscular (i.m.), delivery. In contrast, Ad48 did not elevate transaminases or result in the accumulation of CD11b(+)/Gr-1(+) cells. Collectively, these findings suggest that substantial hexon modifications can lead to unexpected properties which cannot be predicted from parental viruses. Therefore, refined mutations may be preferential for the successful development of targeted vector systems which require i.v. administration.
authors.affiliation: Institute of Cardiovascular and Medical Sciences, MVLS, University of Glasgow, Glasgow, UK.
authors.forename: Lynda
authors.initials: L
authors.lastname: Coughlan
authors.forename: Angela C
authors.initials: AC
authors.lastname: Bradshaw
authors.forename: Alan L
authors.initials: AL
authors.lastname: Parker
authors.forename: Hollie
authors.initials: H
authors.lastname: Robinson
authors.forename: Katie
authors.initials: K
authors.lastname: White
authors.forename: Jerome
authors.initials: J
authors.lastname: Custers
authors.forename: Jaap
authors.initials: J
authors.lastname: Goudsmit
authors.forename: Nico
authors.initials: N
authors.lastname: Van Roijen
authors.forename: Dan H
authors.initials: DH
authors.lastname: Barouch
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Nicklin
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Baker
mesh_terms: D000256:Adenoviridae / Q000276:immunology*; D061605:Administration, Intravenous; D000818:Animals; D005822:Genetic Vectors / Q000008:administration & dosage / Q000009:adverse effects* / Q000276:immunology*; D056945:Hep G2 Cells; D006801:Humans; D008297:Male; D051379:Mice; D060888:Real-Time Polymerase Chain Reaction; D000637:Transaminases / Q000235:genetics / Q000378:metabolism
chemical_list: D000637:Transaminases