Abstract
More than 70 human adenoviruses with type-dependent pathogenicity have been identified but biological information about the majority of these virus types is scarce. Here we employed multiple sequence alignments and structural information to predict receptor usage for the development of an adenoviral vector with novel biological features. We report the generation of a cloned adenovirus based on human adenovirus type 17 (HAdV17) with high sequence homology to the well characterized human adenovirus type 37 (HAdV37) that causes epidemic keratoconjunctivitis (EKC). Our study revealed that human CD46 (CD46) is involved in cell entry of HAdV17. Moreover, we found that HAdV17 infects endothelial cells (EC) in vitro including primary cells at higher efficiencies compared to the commonly used human adenovirus type 5 (HAdV5). Using a human CD46 transgenic mouse model, we observed that HAdV17 displays a broad tropism in vivo after systemic injection and that it transduces ECs in this mouse model. We conclude that the HAdV17-based vector may provide a novel platform for gene therapy.
Highlights
Human adenoviruses are non-enveloped and double-stranded DNA viruses
It is known that CAR can be used for cell entry by several human adenoviruses species and that CD46 is used as a cell surface attachment structure mainly by members of species B adenoviruses
Amino acids of fiber knob proteins known to be involved in receptor binding from X-ray structures were compared to the corresponding ones within the human adenovirus type 17 (HAdV17) sequence
Summary
Human adenoviruses are non-enveloped and double-stranded DNA viruses. To date more than 70 human adenovirus types (HAdV) have been identified[1], which are classified into seven species (A-G) according to hemagglutination and serum neutralization capacities. It remains to be shown whether CD46 is a primary receptor for these viruses and especially for type 48 conflicting information exists[11,12] This type-dependent tropism and the large number of different HAdVs makes adenovirus attractive for therapeutic applications in biomedicine such as gene therapy, oncolytic virotherapy, and vaccination. Pre-existing neutralizing antibodies in up to 90% of the human population can eliminate transduced cells[15,16] Due to these disadvantages, genetic or chemical capsid modifications have been applied as ways to improve features of conventionally used HAdV5 vectors[17,18]. Most studies of human adenoviruses have been based on HAdV5 and a handful of other serotypes because genetic access to other adenovirus types has been difficult To bypass this bottleneck we recently developed new methods to clone and engineer new adenoviral isolates[19]. After performing a cellular screen we established that HAdV17 shows increased transduction efficiencies of endothelial cells in vitro if directly compared to HAdV5
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