Effect of hypoxia on Ad5 infection, transgene expression and replication
Effect of hypoxia on Ad5 infection, transgene expression and replication
复制标题
DOI：
10.1038/sj.gt.3302448
复制
发表时间：
2005-06-01
期刊：
影响因子：
5.1
通讯作者：
Hermiston, TW
中科院分区：
文献类型：
--
作者：
Shen, BH;Hermiston, TW
缺氧是包括心血管疾病和癌症在内的各种人类疾病的共同特征;然而，缺氧对基于Ad的基因疗法的影响尚未被描述。在这项研究中，我们评估了缺氧（1%pO（2））如何影响不同方面的广告为基础的治疗，包括附着和摄取，转基因表达和复制，在一系列的癌细胞系和原代正常细胞。我们发现缺氧对Ad 5附着（柯萨奇病毒和腺病毒受体）和内化（α（v）整合素）蛋白的表达或功能没有显著影响，也没有对人巨细胞病毒驱动的由复制缺陷型Ad携带的外源基因的表达产生显著影响。然而，病毒复制受到缺氧条件的影响。我们的研究揭示了低氧诱导的E1 A水平的降低是在转录后水平介导的。E1 A驱动细胞进入细胞周期的病毒复制最佳S期;因此，E1 A蛋白的减少和缺氧诱导的细胞G1停滞的结合可能是缺氧条件下缺乏有效病毒复制的原因。因此，虽然传统的基于复制缺陷的Ad的载体似乎是用于缺氧相关疾病适应症的可行的递送系统，但我们的研究表明，溶瘤Ad可能需要额外的因子来有效地治疗人类肿瘤的缺氧区域。
Oxygen deprivation ( hypoxia) is a common feature of various human maladies, including cardiovascular diseases and cancer; however, the effect of hypoxia on Ad-based gene therapies has not been described. In this study, we evaluated how hypoxia (1% pO(2)) affects different aspects of Ad-based therapies, including attachment and uptake, transgene expression, and replication, in a series of cancer cell lines and primary normal cells. We found that hypoxia had no significant effect on the expression or function of the Ad5 attachment ( Coxsackievirus and Adenovirus Receptor) and internalization (alpha(v) integrins) proteins, nor on the human cytomegalovirus-driven expression of an exogenous gene carried by a replication-incompetent Ad. Viral replication, however, was compromised by hypoxic conditions. Our studies revealed hypoxia-induced reductions in E1A levels that were mediated at the post-transcriptional level. E1A drives cells into the viral replication optimal S phase of the cell cycle; consequently, the combination of reduced E1A protein and hypoxia-induced G1 arrest of cells may be responsible for the lack of efficient viral replication under hypoxic conditions. Consequently, while traditional replication-incompetent Ad-based vectors appear to be viable delivery systems for hypoxia-associated disease indications, our studies suggest that Oncolytic Ads may need additional factors to efficiently treat hypoxic regions of human tumors.