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Diversity within the adenovirus fiber knob hypervariable loops influences primary receptor interactions

Baker, Alexander T., Greenshields-Watson, Alexander, Coughlan, Lynda, Davies, James A., Uusi-Kerttula, Hanni, Cole, David K., Rizkallah, Pierre J. and Parker, Alan L. 2019. Diversity within the adenovirus fiber knob hypervariable loops influences primary receptor interactions. Nature Communications 10 (1) , -. 10.1038/s41467-019-08599-y

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Abstract

Adenovirus based vectors are of increasing importance for wide ranging therapeutic applications. As vaccines, vectors derived from human adenovirus species D serotypes 26 and 48 (HAdV-D26/48) are demonstrating promising efficacy as protective platforms against infectious diseases. Significant clinical progress has been made, yet definitive studies underpinning mechanisms of entry, infection, and receptor usage are currently lacking. Here, we perform structural and biological analysis of the receptor binding fiber-knob protein of HAdV-D26/48, reporting crystal structures, and modelling putative interactions with two previously suggested attachment receptors, CD46 and Coxsackie and Adenovirus Receptor (CAR). We provide evidence of a low affinity interaction with CAR, with modelling suggesting affinity is attenuated through extended, semi-flexible loop structures, providing steric hindrance. Conversely, in silico and in vitro experiments are unable to provide evidence of interaction between HAdV-D26/48 fiber-knob with CD46, or with Desmoglein 2. Our findings provide insight into the cell-virus interactions of HAdV-D26/48, with important implications for the design and engineering of optimised Ad-based therapeutics.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Medicine
Publisher: Nature Publishing Group
ISSN: 2041-1723
Date of First Compliant Deposit: 28 February 2019
Date of Acceptance: 21 January 2019
Last Modified: 31 Jul 2019 22:25
URI: http://orca.cf.ac.uk/id/eprint/120087

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