Gaggar Anuj, Shayakhmetov Dmitry M, Lieber André
Department of Pathology, University of Washington, Seattle, Washington 98195, USA.
Nat Med. 2003 Nov;9(11):1408-12. doi: 10.1038/nm952. Epub 2003 Oct 19.
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 patients. 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 vectors. Whereas many adenoviruses infect cells through the coxsackievirus and adenovirus receptor (CAR), group B adenoviruses use an alternate, as-yet-unidentified cellular attachment receptor. 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.
B组腺病毒是人类腺病毒科的一个亚属，与免疫功能低下个体（包括骨髓移植受者、癌症患者和艾滋病患者）的多种常致命疾病相关。最近，B组腺病毒衍生物作为有吸引力的基因治疗载体受到关注，因为它们能够转导常用腺病毒载体难以感染的靶组织，如造血干细胞、树突状细胞和恶性肿瘤细胞。许多腺病毒通过柯萨奇病毒和腺病毒受体（CAR）感染细胞，而B组腺病毒则使用另一种尚未确定的细胞附着受体。通过对与B组纤维相互作用的蛋白质进行质谱分析，我们确定人类CD46是大多数B组腺病毒的细胞附着受体。我们发现，人CD46的异位表达使非人类细胞在体外和体内都易受B组病毒感染。此外，siRNA介导的CD46敲低和可溶性CD46形式均能阻断人类细胞系和原代人类细胞的感染。B组腺病毒使用广泛表达的补体调节蛋白CD46作为细胞附着受体这一发现，阐明了B组病毒感染的多种临床表现，并直接关系到这些载体在基因治疗中的应用。
