Defining a novel role for the coxsackie and adenovirus receptor in human adenovirus serotype 5 transduction in vitro in the presence of mouse serum

Lopez-Gordo, E., Doszpoly, A., Duffy, M. R., Coughlan, L., Bradshaw, A. C. , White, K. M., Denby, L., Nicklin, S. A. and Baker, A. H. (2017) Defining a novel role for the coxsackie and adenovirus receptor in human adenovirus serotype 5 transduction in vitro in the presence of mouse serum. Journal of Virology, 91(12), e02487-16. (doi:10.1128/JVI.02487-16) (PMID:28381574) (PMCID:PMC5446653)

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Abstract

Human adenoviral serotype 5 (HAdV-5) vectors have predominantly hepatic tropism when delivered intravascularly, resulting in immune activation and toxicity. Coagulation FX binding to HAdV-5 mediates liver transduction and provides protection from virion neutralisation in mice. FX is dispensable for liver transduction in mice lacking IgM antibodies or complement, suggesting alternative transduction pathways exist. To identify novel factor(s) mediating HAdV-5 FX-independent entry, we investigated HAdV-5 transduction in vitro in the presence of serum from immunocompetent C57BL/6 or immunocompromised mice lacking IgM antibodies (Rag 2-/- and NSG). Sera from all three mouse strains enhanced HAdV-5 transduction of A549 cells. While inhibition of HAdV-5:FX interaction with X-bp inhibited transduction in the presence of C57BL/6 serum, it had negligible effect on the enhanced transduction observed in the presence of Rag 2-/- or NSG serum. Rag 2-/- serum also enhanced transduction of the FX-binding deficient AdT*. Interestingly, Rag 2-/- serum enhanced HAdV-5 transduction in a FX-independent manner in CHO-CAR and SKOV3-CAR cells. Additionally, blockade of CAR with soluble HAdV-5 fiber knob inhibited mouse serum-enhanced transduction in A549 cells, suggesting a potential role for CAR. Transduction of HAdV-5 KO1 and HAdV-5/F35 (CAR-binding deficient) in the presence of Rag 2-/- serum was equivalent to that of HAdV-5, indicating that direct interaction between HAdV-5 and CAR is not required. These data suggest that FX may protect HAdV-5 from neutralization but has minimal contribution to HAdV-5 transduction in the presence of immunocompromised mouse serum. Alternatively, transduction occurs via an unidentified mouse serum protein capable of bridging HAdV-5 to CAR.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Nicklin, Professor Stuart and Bradshaw, Dr Angela and Baker, Professor Andrew and Denby, Dr Laura and White, Miss Katie and Coughlan, Dr Lynda and Duffy, Ms Margaret and Doszpoly, Dr Andor
Authors: Lopez-Gordo, E., Doszpoly, A., Duffy, M. R., Coughlan, L., Bradshaw, A. C., White, K. M., Denby, L., Nicklin, S. A., and Baker, A. H.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Journal of Virology
Publisher:American Society for Microbiology
ISSN:0022-538X
ISSN (Online):1098-5514
Published Online:05 April 2017
Copyright Holders:Copyright © 2017 The Authors
First Published:First published in Journal of Virology 91(12): e02487-16
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
657751Adenovirus and coagulation factor interactions and the impact on virus stability and utility for gene therapyAndrew BakerBiotechnology and Biological Sciences Research Council (BBSRC)BB/L027933/1RI CARDIOVASCULAR & MEDICAL SCIENCES
570791ADVANCE - ADenoViruses as novel clinical treatmentsAndrew BakerEuropean Commission (EC)PITN-GA-2011-290002RI CARDIOVASCULAR & MEDICAL SCIENCES