Enhancement of gene transfer to human myeloid cells by adenovirus-fiber complexes
Enhancement of gene transfer to human myeloid cells by adenovirus-fiber complexes
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DOI：
10.1038/sj.mt.6300048
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发表时间：
2007-03-01
影响因子：
12.4
通讯作者：
Nemerow, Glen R.
中科院分区：
文献类型：
--
作者：
Nepomuceno, Ronald R.;Pache, Lars;Nemerow, Glen R.
目前正在开发用于免疫治疗和疫苗递送的腺病毒（Ad）载体，特别是用于癌症和抗病毒治疗（例如，例如，在一个实施例中，人类免疫缺陷病毒疫苗）。然而，常规的基于Ad 5的载体对髓系抗原呈递细胞如树突状细胞（DC）的低效转导限制了这些应用。DC缺乏科萨基和腺病毒受体，但表达补体调节蛋白家族成员CD 46以及唾液酸糖缀合物，这种情况允许Ad 37型以及大多数亚群B Ad感染。在这项研究中，我们产生了重组腺病毒纤维球（FK）探针Ad 37受体的免疫细胞上的使用。值得注意的是，用Ad 37 FK（37 FK）处理人骨髓细胞增强而不是抑制Ad 5或Ad 37假型病毒体的转导。增强的基因转移是剂量依赖性的，涉及与α（2，6）-连接的唾液酸残基的缔合，并且限于骨髓谱系的血细胞，包括未成熟和成熟DC。我们还提供了37 FK直接与Ad 5病毒颗粒结合的证据，可能作为桥梁促进更大的病毒-细胞相互作用。
Adenoviral (Ad) vectors are currently being developed for immunotherapy and vaccine delivery, particularly for cancer and antiviral treatment ( e. g., human immunodeficiency virus vaccine). However, the inefficient transduction of antigen-presenting cells of myeloid lineage such as dendritic cells (DCs) by conventional Ad5-based vectors limits these applications. DCs lack the coxsackie and adenovirus receptor but express CD46, a member of the family of complement regulatory proteins, as well as sialic acid glycoconjugates, a situation that allows infection by Ad type 37 as well as most subgroup B Ads. In this study, we generated recombinant Ad fiber knobs (FKs) to probe Ad37 receptor usage on immune cells. Remarkably, treatment of human myeloid cells with Ad37 FK (37FK) enhanced, rather than inhibited transduction by Ad5 or Ad37 pseudotyped virions. The enhanced gene transfer was dose dependent, involved association with alpha(2,6)-linked sialic acid residues, and was limited to blood cells of myeloid lineage, including immature and mature DCs. We also provide evidence that 37FK binds directly to Ad5 virus particles, likely acting as a bridge to facilitate greater virus - cell interaction.