Phylogeny and primary structure analysis of fiber shafts of all human adenovirus types for rational design of adenoviral gene-therapy vectors

Abstract

The fiber shaft of human adenoviruses (HAdVs) is essential for bringing the penton base into proximity to the secondary cellular receptor. Fiber shaft sequences of all 53 HAdV types were studied. Phylogeny of the fiber shaft revealed clustering corresponding to the HAdV species concept. An intraspecies recombination hot spot was found at the shaft/knob boundary, a highly conserved sequence stretch. For example, HAdV-D20 clustered with HAdV-D23 in the fiber shaft, but with HAdV-D47 in the fiber knob. Although all shafts exhibited the typical pseudorepeats, amino acid sequence identity was found to be as high as 92 % (interspecies) and 54 % (intraspecies). In contrast to a previous study, a flexibility motif (KXGGLXFD/N) was found in eight HAdV-D types, whereas the putative heparan sulfate-binding site (KKTK) was only found in species HAdV-C. Our results suggest that pseudotyping of gene-therapy vectors at the shaft/ knob boundary is feasible, but that flexibility data of shafts should be considered.

Computational analysis and identification of an emergent human adenovirus pathogen implicated in a respiratory fatality

“…Interestingly, the fiber knob, which acts as the primary ligand for binding to the target cell, differs only in one base, and its imputed amino acid sequence is 100% identical to that of HAdV-D9. This amino acid sequence was also 100% identical to the previously sequenced HAdV-D15/H9 fiber knob (Darr et al, 2009). A comparison of the Bootscan and Simplot analyses of the HAdV-D56 fiber gene (Figs.…”

Cell Entry and Trafficking of Human Adenovirus Bound to Blood Factor X Is Determined by the Fiber Serotype and Not Hexon:Heparan Sulfate Interaction

“…A phylogenetic study of HAdV fiber shaft has revealed the absence of the putative heparan sulfate (HS)-binding site (KKTK motif) in all HAdVs other than species C [69]. The serotype 35 fibers carried by the chimeric HAdV5F35 vector lacked the KKTK motif, and species B HAdV35 has been shown to interact with cellular HSPG via capsid protein domains other than the fiber knob [42].…”

Molecular evolution of human species D adenoviruses

“…Many HAdV-D types bind to the classical adenovirus receptor, coxsackie adenovirus receptor (CAR), but types HAdV-D8, D19, and D37, all associated with epidemic keratoconjunctivitis, appear to bind to CD46 and/or GD1a glycan (Arnberg et al, 2000; Nilsson et al, 2011; Wu et al, 2004). Recently, recombination was proposed to occur at the shaft/knob boundary, (Darr et al, 2009) (Fig. 4C).…”