Journal
JOURNAL OF VIROLOGY
Volume 82, Issue 21, Pages 10567-10579Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/JVI.01308-08
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Funding
- NIH [HLA078836, AI065429]
- Deutsche Forschungsgemeinschaft [SFB685, STE1163]
- BBSRC [BB/E02145X/1] Funding Source: UKRI
- MRC [MC_U120074259] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/E02145X/1] Funding Source: researchfish
- Medical Research Council [MC_U120074259] Funding Source: researchfish
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Gene transfer vectors containing adenovirus (Ad) serotype 35 (Ad35) fibers have shown promise for cancer and stem cell gene therapy. In this study, we attempted to improve the in vitro and in vivo infection properties of these vectors by increasing their affinity to the Ad35 fiber receptor CD46. We constructed Ad vectors containing either the wild-type Ad35 fiber knob (Ad5/35) or Ad35 knob mutants with 4-fold- and 60-fold-higher affinity to CD46 (Ad5/35+ and Ad5/35++, respectively). In in vitro studies with cell lines, the higher affinities of Ad5/35+ and Ad5/35++ to CD46 did not translate into correspondingly higher transduction efficiencies, regardless of the CD46 receptor density present on cells. However, in vivo, in a mouse model with preestablished CD46(high) liver metastases, intravenous injection of Ad5/35++ resulted in more-efficient tumor cell transduction. We conclude that Ad5/35 vectors with increased affinity to CD46 have an advantage in competing with non-CD46-mediated sequestration of vector particles after intravenous injection.
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