EXPRESSION OF ALPHA(NU)BETA(5) INTEGRIN IS NECESSARY FOR EFFICIENT ADENOVIRUS-MEDIATED GENE-TRANSFER IN THE HUMAN AIRWAY
EXPRESSION OF ALPHA(NU)BETA(5) INTEGRIN IS NECESSARY FOR EFFICIENT ADENOVIRUS-MEDIATED GENE-TRANSFER IN THE HUMAN AIRWAY
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DOI：
10.1128/jvi.69.10.5951-5958.1995
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发表时间：
1995-10-01
影响因子：
5.4
通讯作者：
WILSON, JM
中科院分区：
文献类型：
--
作者：
GOLDMAN, MJ;WILSON, JM
重组腺病毒正被用于囊性纤维性肺疾病的基因治疗，目的是通过将病毒直接注射到呼吸道来重建囊性纤维化跨膜传导调节因子在肺上皮细胞中的表达。重组腺病毒的治疗潜力在一定程度上受到基因转移相对低效的限制。这项研究使用人支气管异种移植模型来研究腺病毒在人类呼吸道中的感染，试图确定限制基因转移的分子事件。我们对人类呼吸道的研究证实了先前对细胞系的观察，这些观察表明腺病毒的进入有一个两步的过程，首先是病毒通过纤维蛋白与细胞结合，然后通过细胞整合素和五肽碱基中的RGD基序(Arg-Gly-Asp)之间的相互作用继续内化。此外，异种移植中上皮细胞的成熟程度对基因转移有很大的影响。未分化上皮细胞表达高水平的α(V)β(5)整合素，容易被重组腺病毒感染；过量的纤维可完全抑制基因转移，RGD多肽和α(V)β(5)整合素抗体可部分抑制基因转移。假复层上皮在分化的柱状细胞中不表达α(V)β(5)整合素，对腺病毒介导的基因转移具有相对抵抗力；很少发生的基因转移可被纤维抑制，但不受RGD肽或α(V)β(5)整合素抗体的抑制。这些研究表明，整合素在人呼吸道上皮细胞中的表达限制了重组腺病毒的基因转移效率。然而，低水平的基因转移可以通过α(V)β(5)整合素非依赖的途径发生在完全成熟的上皮细胞中。
Recombinant adenoviruses are being evaluated for gene therapy of cystic fibrosis lung disease with the goal of reconstituting the expression of the cystic fibrosis transmembrane conductance regulator in pulmonary epithelia by direct administration of the virus into the airway. The therapeutic potential of recombinant adenoviruses is limited in part by the relative inefficiency by which gene transfer occurs. This study uses a human bronchial xenograft model to study adenovirus infection in the human airway in an attempt to define the molecular events that limit gene transfer. Our studies of the human airway confirm previous observations of cell lines that have indicated a two-step process for adenovirus entry, which begins with the binding of the virus to the cell through the fiber protein and continues with internalization via interactions among cellular integrins and an RGD motif (Arg-Gly-Asp) in the penton base. Furthermore, the level of maturity of the epithelia in xenografts has a major impact on gene transfer. Undifferentiated epithelia express high levels of alpha(v) beta(5) integrins and are easily infected with recombinant adenoviruses; gene transfer is completely inhibited with excess fiber and partially inhibited with RGD peptide and alpha(v) beta(5) integrin antibody. Pseudostratified epithelia do not express alpha(v) beta(5) integrin in differentiated columnar cells and are relatively resistant to adenovirus-mediated gene transfer; what little gene transfer occurs is inhibited by fiber but not by RGD peptide or alpha(v) beta(5) integrin antibody. These studies suggest that the expression of integrins in human airway epithelia limits the efficiency of gene transfer with recombinant adenoviruses. However, low-level gene transfer can occur in fully mature epithelia through alpha(v) beta(5) integrin-independent pathways.