Abstract
Group B adenoviruses, a subgenus of human Adenoviridae, are associated with a variety of often-fatal illnesses in immunocompromised individuals, including bone marrow transplant recipients and cancer and AIDS patients1,2,3. Recently, group B adenovirus derivatives have gained interest as attractive gene therapy vectors because they can transduce target tissues, such as hematopoietic stem cells, dendritic cells and malignant tumor cells, that are refractory to infection by commonly used adenoviral vectors4,5,6. Whereas many adenoviruses infect cells through the coxsackievirus and adenovirus receptor (CAR), group B adenoviruses use an alternate, as-yet-unidentified cellular attachment receptor7,8,9,10. Using mass spectrometric analysis of proteins interacting with a group B fiber, we identified human CD46 as a cellular attachment receptor for most group B adenoviruses. We show that ectopic expression of human CD46 rendered nonhuman cells susceptible to infection with group B viruses in vitro and in vivo. In addition, both siRNA-mediated knockdown of CD46 and a soluble form of CD46 blocked infection of human cell lines and primary human cells. The discovery that group B adenoviruses use CD46, a ubiquitously expressed complement regulatory protein, as a cellular attachment receptor elucidates the diverse clinical manifestation of group B virus infections, and bears directly on the application of these vectors for gene therapy.
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Acknowledgements
The authors thank J.P. Atkinson, K. Liszewski and M. Leung for CD46-expressing cell lines, soluble CD46 constructs and CD46 transgenic mice; M. Sadilek for expert help with mass spectrometry; S. Ni for help with mice; Z.-Y. Li for help with confocal microscopy; and D. Stone, M. Mealiffe and S. Fields for critical reviewing of the manuscript. This work is supported by National Institutes of Health grants HL-00-008 and DK47754, and grants from the Doris Duke and Avon Foundations. D.M.S. is supported by the Cystic Fibrosis Foundation. A.G. is supported by fellowships from the Medical Scientist Training Program, Poncin and the Achievement Award for College Scientists fellowships.
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Gaggar, A., Shayakhmetov, D. & Lieber, A. CD46 is a cellular receptor for group B adenoviruses. Nat Med 9, 1408–1412 (2003). https://doi.org/10.1038/nm952
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DOI: https://doi.org/10.1038/nm952
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