Human CD46-transgenic mice in studies involving replication-incompetent adenoviral type 35 vectors.
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.
Verhaagh
Sandra
S
Crucell Holland BV, Archimedesweg 4, 2333 CN Leiden, The Netherlands.
de Jong
Esmeralda
E
Crucell Holland BV, Archimedesweg 4, 2333 CN Leiden, The Netherlands.
Goudsmit
Jaap
J
Crucell Holland BV, Archimedesweg 4, 2333 CN Leiden, The Netherlands.
Lecollinet
Sylvie
S
Ecole National Veterinaire d'Alfort, Alfort, France.
Gillissen
Gert
G
Crucell Holland BV, Archimedesweg 4, 2333 CN Leiden, The Netherlands.
de Vries
Margreet
M
Gaubius Laboratory, TNO Leiden, The Netherlands.
van Leuven
Kees
K
Gaubius Laboratory, TNO Leiden, The Netherlands.
Que
Ivo
I
Department of Endocrinology, Leiden University Medical Centre, Leiden, The Netherlands.
Ouwehand
Krista
K
Crucell Holland BV, Archimedesweg 4, 2333 CN Leiden, The Netherlands.
Mintardjo
Ratna
R
Crucell Holland BV, Archimedesweg 4, 2333 CN Leiden, The Netherlands.
Weverling
Gerrit Jan
GJ
Crucell Holland BV, Archimedesweg 4, 2333 CN Leiden, The Netherlands.
Radošević
Katarina
K
Crucell Holland BV, Archimedesweg 4, 2333 CN Leiden, The Netherlands.
Richardson
Jennifer
J
Ecole National Veterinaire d'Alfort, Alfort, France.
Eloit
Marc
M
Ecole National Veterinaire d'Alfort, Alfort, France.
Lowik
Clemens
C
Department of Endocrinology, Leiden University Medical Centre, Leiden, The Netherlands.
Quax
Paul
P
Gaubius Laboratory, TNO Leiden, The Netherlands.
Havenga
Menzo
M
Crucell Holland BV, Archimedesweg 4, 2333 CN Leiden, The Netherlands.
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
D051916:Membrane Cofactor Protein