Diversity within the Adenovirus fiber knob hypervariable loops influences primary receptor interactions.
Alexander T. Baker, Alex Greenshields-Watson, Lynda Coughlan, James A. Davies, Hanni Uusi-Kerttula1, David K. Cole, Pierre Rizkallah, Alan L. Parker
Received Date: 22nd August 2018
Adenovirus based vectors are of increasing relevance for wide ranging therapeutic applications. As vaccines, vectors derived from species D serotypes 26 and 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 performed structural and biological analysis of the receptor binding fiber-knob protein of Ad26/48, reporting crystal structures, and modelling putative interactions with two previously suggested attachment receptors, CD46 and CAR. We provide clear evidence of 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 were unable to provide evidence of interaction between Ad26/48 fiber-knob with CD46. Our findings provide new insight to the cell-virus interactions of Ad26/48, with important implications for the design and engineering of optimised Ad-based therapeutics.
Read in full at bioRxiv.
This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.