Reinhart Bonnie, Mazzacurati Lucia, Forero Adriana, Hong Chang-Sook, Eguchi Junichi, Okada Hideho, Fellows Wendy, Niranjan Ajay, Cohen Justus B, Glorioso Joseph C, Grandi Paola
Department of Microbiology and Molecular Genetics, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Adv Virol. 2012;2012:815465. doi: 10.1155/2012/815465. Epub 2012 Aug 13.
Successful oncolytic virus treatment of malignant glioblastoma multiforme depends on widespread tumor-specific lytic virus replication and escape from mitigating innate immune responses to infection. Here we characterize a new HSV vector, JD0G, that is deleted for ICP0 and the joint sequences separating the unique long and short elements of the viral genome. We observed that JD0G replication was enhanced in certain glioblastoma cell lines compared to HEL cells, suggesting that a vector backbone deleted for ICP0 may be useful for treatment of glioblastoma. The innate immune response to virus infection can potentially impede oncolytic vector replication in human tumors. Indoleamine-2,3-dioxygenase (IDO) is expressed in response to interferon γ (IFNγ) and has been linked to both antiviral functions and to the immune escape of tumor cells. We observed that IFNγ treatment of human glioblastoma cells induced the expression of IDO and that this expression was quelled by infection with both wild-type and JD0G viruses. The role of IDO in inhibiting virus replication and the connection of this protein to the escape of tumor cells from immune surveillance suggest that IDO downregulation by HSV infection may enhance the oncolytic activity of vectors such as JD0G.
成功使用溶瘤病毒治疗多形性恶性胶质母细胞瘤取决于病毒在肿瘤中广泛的特异性裂解复制以及避免机体对感染产生先天性免疫反应。在此，我们鉴定了一种新的单纯疱疹病毒（HSV）载体JD0G，该载体缺失了ICP0以及病毒基因组中分隔独特长片段和短片段的连接序列。我们观察到，与HEL细胞相比，JD0G在某些胶质母细胞瘤细胞系中的复制增强，这表明缺失ICP0的载体骨架可能对胶质母细胞瘤的治疗有用。机体对病毒感染的先天性免疫反应可能会阻碍溶瘤载体在人类肿瘤中的复制。吲哚胺-2,3-双加氧酶（IDO）在受到干扰素γ（IFNγ）刺激后表达，并且与抗病毒功能以及肿瘤细胞的免疫逃逸均有关联。我们观察到，用IFNγ处理人类胶质母细胞瘤细胞会诱导IDO的表达，而野生型病毒和JD0G病毒感染均可抑制这种表达。IDO在抑制病毒复制中的作用以及该蛋白与肿瘤细胞免疫逃逸的关联表明，HSV感染下调IDO可能会增强诸如JD0G等载体的溶瘤活性。
