title: Human CD46-transgenic mice in studies involving replication-incompetent adenoviral type 35 vectors.
abstract: Wild-type strains of mice do not express CD46, a high-affinity receptor for human group B adenoviruses including type 35. Therefore, studies performed to date in mice using replication-incompetent Ad35 (rAd35) vaccine carriers may underestimate potency or result in altered vector distribution. Here, it is reported that CD46 transgenic mice (MYII-strain) express CD46 in all major organs and that it functions as a receptor for rAd35 vectors. Similar to monkeys and humans, MYII mice highly express CD46 in their lungs and kidneys and demonstrate low expression in muscle. Upon intravenous administration, rAd35 vector genomes as well as expression are detected in lungs of MYII mice, in contrast to wild-type littermates. Expression was predominantly detected in lung epithelial cells. Upon intramuscular administration, the initial level of luciferase expression is higher in MYII mice as compared with wild-type littermates, in spite of the fact that CD46 expression is low in muscle of MYII mice. The higher level of expression in muscle of MYII mice results in prolonged gene expression as assessed by CCD camera imaging for luciferase activity. Finally, a significant dose-sparing effect in MYII mice as compared with wild-type littermates on anti-SIVgag CD8+ T-cell induction following intramuscular vaccination with an rA35.SIVgag vaccine was observed. This dose-sparing effect was also observed when reinfusing dendritic cells derived from MYII mice after exposure to rAd35.SIVgag vaccine as compared with rAd35.SIVgag exposed dendritic cells from wild-type littermates. It was concluded that MYII mice represent an interesting preclinical model to evaluate potency and safety of rAd35 vectors.
authors.affiliation: Crucell Holland BV, Archimedesweg 4, 2333 CN Leiden, The Netherlands.
authors.forename: Sandra
authors.initials: S
authors.lastname: Verhaagh
authors.affiliation: Crucell Holland BV, Archimedesweg 4, 2333 CN Leiden, The Netherlands.
authors.forename: Esmeralda
authors.initials: E
authors.lastname: de Jong
authors.affiliation: Crucell Holland BV, Archimedesweg 4, 2333 CN Leiden, The Netherlands.
authors.forename: Jaap
authors.initials: J
authors.lastname: Goudsmit
authors.affiliation: Ecole National Veterinaire d'Alfort, Alfort, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Lecollinet
authors.affiliation: Crucell Holland BV, Archimedesweg 4, 2333 CN Leiden, The Netherlands.
authors.forename: Gert
authors.initials: G
authors.lastname: Gillissen
authors.affiliation: Gaubius Laboratory, TNO Leiden, The Netherlands.
authors.forename: Margreet
authors.initials: M
authors.lastname: de Vries
authors.affiliation: Gaubius Laboratory, TNO Leiden, The Netherlands.
authors.forename: Kees
authors.initials: K
authors.lastname: van Leuven
authors.affiliation: Department of Endocrinology, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Ivo
authors.initials: I
authors.lastname: Que
authors.affiliation: Crucell Holland BV, Archimedesweg 4, 2333 CN Leiden, The Netherlands.
authors.forename: Krista
authors.initials: K
authors.lastname: Ouwehand
authors.affiliation: Crucell Holland BV, Archimedesweg 4, 2333 CN Leiden, The Netherlands.
authors.forename: Ratna
authors.initials: R
authors.lastname: Mintardjo
authors.affiliation: Crucell Holland BV, Archimedesweg 4, 2333 CN Leiden, The Netherlands.
authors.forename: Gerrit Jan
authors.initials: GJ
authors.lastname: Weverling
authors.affiliation: Crucell Holland BV, Archimedesweg 4, 2333 CN Leiden, The Netherlands.
authors.forename: Katarina
authors.initials: K
authors.lastname: Radošević
authors.affiliation: Ecole National Veterinaire d'Alfort, Alfort, France.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Richardson
authors.affiliation: Ecole National Veterinaire d'Alfort, Alfort, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Eloit
authors.affiliation: Department of Endocrinology, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Clemens
authors.initials: C
authors.lastname: Lowik
authors.affiliation: Gaubius Laboratory, TNO Leiden, The Netherlands.
authors.forename: Paul
authors.initials: P
authors.lastname: Quax
authors.affiliation: Crucell Holland BV, Archimedesweg 4, 2333 CN Leiden, The Netherlands.
authors.forename: Menzo
authors.initials: M
authors.lastname: Havenga
mesh_terms: D000260:Adenoviruses, Human / Q000235:genetics / Q000502:physiology*; D000818:Animals; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D051916:Membrane Cofactor Protein / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D014779:Virus Replication
chemical_list: D051916:Membrane Cofactor Protein