Designing Herpes Viruses as Oncolytics.
Designing Herpes Viruses as Oncolytics.
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DOI：
10.1038/mto.2015.10
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Rabkin SD
中科院分区：
文献类型：
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作者：
Peters C;Rabkin SD
溶瘤单纯疱疹病毒(OHSV)是最早的基因工程溶瘤病毒之一。由于单纯疱疹病毒是一种自然的人类病原体，可能会导致严重的疾病，因此为了安全起见，必须对其进行基因工程改造或显著减毒。在这里，我们提出了HSV-1基因频繁突变以赋予溶瘤活性的功能的详细解释。这些基因对组织培养细胞的生长不是必需的，但对有丝分裂后细胞的生长很重要，干扰固有的抗病毒和先天免疫反应，或引起病理，这些功能对于癌细胞的复制是必不可少的。了解这些基因的功能有助于在知情的情况下创造新的OHSV，具有更好的治疗效果。病毒感染和复制也可以通过肿瘤选择性受体结合和转录-或转录后miRNA靶向分别定向到癌细胞。除了OHSV对受感染的癌细胞和肿瘤的直接影响外，OHSV还可以携带转基因，这些转基因是：追踪病毒复制和传播的报告基因；杀死未感染的肿瘤细胞的细胞毒素；刺激抗肿瘤免疫的免疫调节剂；或改变肿瘤微环境，促进病毒传播或抑制肿瘤生长。除了HSV-1，还讨论了其他甲型疱疹病毒的溶瘤活性。
Oncolytic herpes simplex virus (oHSV) was one of the first genetically-engineered oncolytic viruses. Because HSV is a natural human pathogen that can cause serious disease, it is incumbent that it can be genetically-engineered or significantly attenuated for safety. Here, we present a detailed explanation of the functions of HSV-1 genes frequently mutated to endow oncolytic activity. These genes are nonessential for growth in tissue culture cells but are important for growth in postmitotic cells, interfering with intrinsic antiviral and innate immune responses or causing pathology, functions dispensable for replication in cancer cells. Understanding the function of these genes leads to informed creation of new oHSVs with better therapeutic efficacy. Virus infection and replication can also be directed to cancer cells through tumor-selective receptor binding and transcriptional- or post-transcriptional miRNA-targeting, respectively. In addition to the direct effects of oHSV on infected cancer cells and tumors, oHSV can be “armed” with transgenes that are: reporters, to track virus replication and spread; cytotoxic, to kill uninfected tumor cells; immune modulatory, to stimulate antitumor immunity; or tumor microenvironment altering, to enhance virus spread or to inhibit tumor growth. In addition to HSV-1, other alphaherpesviruses are also discussed for their oncolytic activity.