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.
Highlights
Adenovirus based vectors are of increasing importance for wide ranging therapeutic applications
Utilising surface plasmon resonance (SPR), we investigate the potential for HAdV-D26 and HAdV-D48 to interact with Desmoglein 2
The tree based upon the fiberknob domain (Fig. 1b) shows the species D adenoviruses forming a greater number of sub-groups than in the whole genome tree suggesting greater diversity in the receptors of this species than might be expected when comparing serotypes
Summary
Adenovirus based vectors are of increasing importance for wide ranging therapeutic applications. Adenoviruses are increasingly important vectors for wideranging therapeutic interventions, from gene delivery and oncolytic agents to platforms for vaccine applications[1,2,3] As vaccine vectors, their use clinically has been popularised by their excellent safety profile coupled with their ability to induce robust cellular and humoral immunogenicity in humans[4]. Vectors under development include those based on species D serotypes including HAdV-D26, which has entered Phase-III clinical trials as an Ebola vaccine and recently reported promising immunogenicity in an HIV trial. We employ an integrative workflow utilising X-ray crystallography, in silico modelling, and in vitro assays to dissect previous findings[16,17] suggesting interactions by HAdV-D26 and HAdV-D48 with Coxsackie and Adenovirus Receptor (CAR)[5,18] and CD46 (Membrane Cofactor Protein, MCP)[16,17,19,20,21]. Our findings shed new light on the cell–virus interactions of adenovirus and have potential implications for the design and engineering of optimised HAdV-based therapeutics, both for vaccine applications and oncolytic development, allowing us to minimise off-target or undesirable interactions in vivo
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