Downregulation of human CD46 by adenovirus serotype 35 vectors
Downregulation of human CD46 by adenovirus serotype 35 vectors
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DOI：
10.1038/sj.gt.3302946
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发表时间：
2007-03
期刊：
影响因子：
5.1
通讯作者：
F. Sakurai;K. Akitomo;K. Kawabata;T. Hayakawa;H. Mizuguchi
中科院分区：
文献类型：
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作者：
F. Sakurai;K. Akitomo;K. Kawabata;T. Hayakawa;H. Mizuguchi
人CD 46（膜辅因子蛋白）作为多种病原体的受体，包括麻疹病毒株、人疱疹病毒6型和奈瑟氏球菌，在被这些病原体感染后从细胞表面迅速下调。在这里，我们报告说，复制缺陷型腺病毒（Ad）血清型35（Ad 35）载体，这属于亚组B和识别人CD 46作为受体，下调CD 46感染后。人外周血单个核细胞表面CD 46的表达下降，感染后6小时可检测到，并在感染后12小时达到最大值（72%）。去除Ad 35载体后，Ad 35载体诱导的表面CD 46水平下调逐渐恢复，然而，即使在去除后96 h也未观察到CD 46表达的完全恢复。在与携带Ad 35纤维蛋白的纤维取代的Ad血清型5（Ad 5）载体、经紫外线照射的Ad 35载体和重组Ad 35纤维球蛋白孵育后，CD 46的表面表达也降低;相反，常规Ad 5载体不诱导表面CD 46下调，提示Ad 35的纤维球蛋白在表面CD 46密度的下调中起关键作用。这些结果具有重要意义的基因治疗，利用CD 46的广告载体和与CD 46相互作用的广告的发病机制。
Human CD46 (membrane cofactor protein), which serves as a receptor for a variety of pathogens, including strains of measles virus, human herpesvirus type 6 and Neisseria, is rapidly downregulated from the cell surface following infection by these pathogens. Here, we report that replication-incompetent adenovirus (Ad) serotype 35 (Ad35) vectors, which belong to subgroup B and recognize human CD46 as a receptor, downregulate CD46 following infection. A decline in the surface expression of CD46 in human peripheral blood mononuclear cells was detectable 6 h after infection, and reached maximum (72%) 12 h after infection. Ad35 vector-induced downregulation of surface CD46 levels gradually recovered after the removal of Ad35 vectors, however, complete recovery of CD46 expression was not observed even at 96 h after removal. The surface expression of CD46 was also reduced after incubation with fiber-substituted Ad serotype 5 (Ad5) vectors bearing Ad35 fiber proteins, ultraviolet-irradiated Ad35, vectors and recombinant Ad35 fiber knob proteins; in contrast, conventional Ad5 vectors did not induce surface CD46 downregulation, suggesting that the fiber knob protein of Ad35 plays a crucial role in the downregulation of surface CD46 density. These results have important implications for gene therapy using CD46-utilizing Ad vectors and for the pathogenesis of Ads that interact with CD46.