Abstract
Aim: To reconstruct the ancestral sequence of human adenoviral hexon protein by combining sequence variations and structural information. And to provide a candidate hexon protein for developing new adenoviral vector capable of escaping the pre-existing immunity in healthy populations.Methods: The sequences of 74 adenovirus-type strains were used to predict the ancestral sequence of human adenovirus hexon protein using FastML and MEGA software. The three-dimensional structure model was built using homology modeling methods. The immunological features of ancestral loop 1 and loop 2 regions of sequences were tested using protein segments expressed in a prokaryotic expression system and polypeptides synthesized with human serum samples.Results: The tower region of the hexon protein had the highest sequence variability, while the neck and base regions remained constant among different types. The modern strains successfully predicted the common ancestral sequence of the human adenovirus hexon. The positive sera against neutralizing epitopes on the common ancestor of adenoviral hexon were relatively rare among healthy adults.Conclusion: The existing strains inferred the common ancestor of human adenoviruses, with epitopes never observed in the current human strains. The predicted common ancestor hexon is a good prospect in the improvement of adenovirus vectors.
Highlights
Adenovirus is among the most important model organisms in medical research
Seventeen of the 44 products have >80% average homology, and 20 products have 70–80% average homology while the rest are below 70%
The IVa2 protein has the highest homology among the products with known functions
Summary
Adenovirus is among the most important model organisms in medical research. In healthy adults, adenoviruses cause transient or mild infections, making adenoviruses good candidates for gene therapy, immunotherapy, or immunization (Khanal et al, 2018). The pre-existing adenovirus immunity in healthy populations. Re-designing the adenoviral structural proteins will improve the vectors and probably escape pre-existing immunity. The adenovirus forms an icosahedral nucleocapsid with 252 capsids, including 240 hexons and 12 pentons, and each penton is connected with one or two fibers. The X-ray diffraction determined the threedimensional structures of the three major structural adenoviral proteins; hexon, penton, and fiber. The hexon base area is β sheets and α helices, while the tower region consists of random coils and corners. The human adenoviral penton is a homopentamer with five monomers, divided into a base and a top. The C-terminus has two sets of anti-parallel β sheets attached to form a fiber knob. The fiber knob is the ligand that binds adenovirus capsid to the host cell receptors (Persson et al, 2009)
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