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

Authors:
Lynda Coughlan
Lynda Coughlan
The Jenner Institute
United Kingdom
James A Davies
James A Davies
University of Calgary
Canada
Hanni Uusi-Kerttula
Hanni Uusi-Kerttula
Icahn School of Medicine at Mount Sinai
United States
David K Cole
David K Cole
Cardiff University School of Medicine
United Kingdom
Pierre J Rizkallah
Pierre J Rizkallah
Cardiff University School of Medicine
United Kingdom
Alan L Parker
Alan L Parker
CRC Institute for Cancer Studies

Nat Commun 2019 02 14;10(1):741. Epub 2019 Feb 14.

Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, CF14 4XN, UK.

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.

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Source
http://dx.doi.org/10.1038/s41467-019-08599-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6376029PMC
February 2019
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