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The fiber knob protein of human adenovirus type 49 mediates highly efficient and promiscuous infection of cancer cell lines using a novel cell entry mechanism

Baker, Alexander T., Davies, James A., Bates, Emily A., Moses, Elise, Mundy, Rosie M., Marlow, Gareth, Cole, David K., Bliss, Carly M., Rizkallah, Pierre J. and Parker, Alan L. 2021. The fiber knob protein of human adenovirus type 49 mediates highly efficient and promiscuous infection of cancer cell lines using a novel cell entry mechanism. Journal of Virology 95 (4) , e01849-20. 10.1128/JVI.01849-20

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Abstract

The human adenovirus (HAdV) phylogenetic tree is diverse, divided across seven species and comprising over 100 individual types. Species D HAdV are rarely isolated with low rates of pre-existing immunity, making them appealing for therapeutic applications. Several species D vectors have been developed as vaccines against infectious diseases where they induce robust immunity in pre-clinical models and early phase clinical trials. However, many aspects of the basic virology of species D HAdV, including their basic receptor usage and means of cell entry, remain understudied. Here, we investigated HAdV-D49, which previously has been studied for vaccine and vascular gene transfer applications. We generated a pseudotyped HAdV-C5 presenting the HAdV-D49 fiber knob protein (HAdV-C5/D49K). This pseudotyped vector was efficient at infecting cells devoid of all known HAdV receptors, indicating HAdV-D49 uses an unidentified cellular receptor. Conversely, a pseudotyped vector presenting the fiber knob protein of the closely related HAdV-D30 (HAdV-C5/D30K), differing in four amino acids to HAdV-D49, failed to demonstrate the same tropism. These four amino acid changes resulted in a change in isoelectric point of the knob protein, with HAdV-D49K possessing a basic apical region compared to a more acidic region in HAdV-D30K. Structurally and biologically we demonstrate that HAdV-D49 knob protein is unable to engage CD46, while potential interaction with CAR is extremely limited by extension of the DG loop. HAdV-C5/49K efficiently transduced cancer cell lines of pancreatic, breast, lung, oesophageal and ovarian origin, indicating it may have potential for oncolytic virotherapy applications, especially for difficult to transduce tumor types.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Additional Information: This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.
Publisher: American Society for Microbiology
ISSN: 0022-538X
Funders: Wellcome Trust
Date of First Compliant Deposit: 3 December 2020
Date of Acceptance: 19 November 2020
Last Modified: 18 Mar 2021 10:06
URI: http://orca.cardiff.ac.uk/id/eprint/136755

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