Phylogeny and Primary Structure Analysis of Fiber Shafts of All Human Adenovirus Types for Rational Design of Adenoviral Gene Therapy Vectors

Institut für Virologie, Medizinische Hochschule Hannover, D-30625 Hannover, Germany.
Journal of General Virology (Impact Factor: 3.18). 09/2009; 90(Pt 12):2849-54. DOI: 10.1099/vir.0.014514-0
Source: PubMed


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.

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Available from: Sebastian Darr
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    • "The fiber consists of a shaft and knob. Analysis of Adv fibers showed that the Adv-D fiber shaft bears fiber flexibility motifs KLGxGLxF[DN]and KxGGLxF[DN], which may have roles in interactions with host cells[50]. "

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    • "The recombination event, presumably in the 1970s (Houng et al., 2006), likely enables these HAdV-E4 strains to compete successfully, comprisng up to 499.8% of the HAdVcaused ARD cases in the U.S. military prior to and driving the recent reinstatement of a specific vaccine against it (Blasiole et al., 2004). Paradoxically, despite this role as a human pathogen, HAdVs are also important biomedical tools as vectors for epitope and gene delivery (Darr et al., 2009; Fujishiro et al., 2005; Graham and Prevec, 1992; Stone et al., 2006). To bypass pre-existing immune responses, recent attention to non-human simian adenoviruses (SAdVs) as potential gene vectors has serendipitously brought additional genomes into the data set (Roy et al., 2004a, 2004b, 2012, 2009, 2006). "
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    ABSTRACT: Emergent human and simian adenoviruses (HAdVs) may arise from genome recombination. Computational analysis of SAdV type 35 reveals a genome comprising a chassis with elements mostly from two simian adenoviruses, SAdV-B21 and -B27, and regions of high sequence similarity shared with HAdV-B21 and HAdV-B16. Although recombination direction cannot be determined, the presence of these regions suggests prior infections of humans by an ancestor of SAdV-B35, and/or vice versa. Absence of this virus in humans may reflect non-optimal conditions for zoonosis or incomplete typing, e.g., limited epitope-based. The presence of both a critical viral replication element found in HAdV genomes and genes that are highly similar to ones in HAdVs suggest the potential to establish in a human host. This allows a prediction that this virus may be a nascent human respiratory pathogen. The recombination potential of human and simian adenovirus genomes should be considered in the use of SAdVs as vectors for gene delivery in humans.
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    • "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]. "
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