CD46 is a cellular receptor for group B adenoviruses
CD46 is a cellular receptor for group B adenoviruses
复制标题
DOI：
10.1038/nm952
复制
发表时间：
2003-11-01
期刊：
影响因子：
82.9
通讯作者：
Lieber, A
中科院分区：
文献类型：
--
作者：
Gaggar, A;Shayakhmetov, DM;Lieber, A
B组腺病毒是人腺病毒科的一个亚属，与免疫功能低下个体中的多种通常致命的疾病相关，包括骨髓移植受体和癌症及AIDS患者（1-3）。最近，B组B腺病毒衍生物作为有吸引力的基因治疗载体而引起了人们的兴趣，因为它们可以转导对常用腺病毒载体感染难治的靶组织，例如造血干细胞、树突状细胞和恶性肿瘤细胞（4-6）。尽管许多腺病毒通过柯萨奇病毒和腺病毒受体（CAR）感染细胞，但B组腺病毒使用替代的、尚未鉴定的细胞附着受体（7-10）。使用质谱分析与B组纤维相互作用的蛋白质，我们确定了人CD 46作为大多数B组腺病毒的细胞附着受体。我们发现，异位表达的人CD 46呈现非人细胞在体外和体内容易感染B组病毒。此外，siRNA介导的CD 46敲低和可溶形式的CD 46都阻断了人细胞系和原代人细胞的感染。B组腺病毒使用CD 46（一种普遍表达的补体调节蛋白）作为细胞附着受体的发现阐明了B组病毒感染的多种临床表现，并且直接关系到这些载体用于基因治疗的应用。
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(1-3). 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 vectors(4-6). Whereas many adenoviruses infect cells through the coxsackievirus and adenovirus receptor (CAR), group B adenoviruses use an alternate, as-yet-unidentified cellular attachment receptor(7-10). 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.