Zhou Guoying, Roizman Bernard
The Marjorie B. Kovler Viral Oncology Laboratories, University of Chicago, 910 East 58th Street, Chicago, IL 60637, USA.
Proc Natl Acad Sci U S A. 2006 Apr 4;103(14):5508-13. doi: 10.1073/pnas.0601258103. Epub 2006 Mar 22.
Current design of genetically engineered viruses for selective destruction of cancer cells is based on the observation that attenuated viruses replicate better in tumor cells than in normal cells. The ideal virus, however, is one that can infect only cancer cells by virtue of altered host range. Such a virus can be made more robust than the highly attenuated viruses used in clinical trials. Earlier, we reported the construction of a recombinant herpes simplex virus 1 (R5111) in which the capacity to bind heparan sulfate was disabled and which contained a chimeric IL-13-glycoprotein D that enabled the virus to infect cells expressing the IL-13alpha2 receptor (IL-13Ralpha2) commonly found on the surface of malignant glioblastomas or high-grade astrocytomas. In the earlier report, we showed that the recombinant R5111 was able to enter and infect cells via the interaction of the chimeric glycoprotein D with IL-13Ralpha2 but that the virus retained the capacity to bind and replicate in cells expressing the natural viral receptors HveA or nectin-1. Here, we report the construction of a recombinant virus (R5141) that can only enter and replicate in cells that express the IL-13Ralpha2. The recombinant R5141 does not depend on endocytosis to infect cells. It does not infect cells expressing HveA or nectin-1 receptors or cells expressing IL-13Ralpha2 that had been exposed to soluble IL-13 before infection. The studies described here show that the host range of herpes simplex viruses can be altered by genetic manipulation to specifically target cancer cells.
减毒病毒在肿瘤细胞中的复制能力比在正常细胞中更强。然而，理想的病毒是一种能够凭借改变的宿主范围仅感染癌细胞的病毒。这样的病毒可以比临床试验中使用的高度减毒病毒更具活力。此前，我们报道了一种重组单纯疱疹病毒1（R5111）的构建，该病毒中结合硫酸乙酰肝素的能力被破坏，并且包含一种嵌合的IL-13-糖蛋白D，使得该病毒能够感染表达IL-13α2受体（IL-13Rα2）的细胞，这种受体常见于恶性胶质母细胞瘤或高级别星形细胞瘤的表面。在早期报告中，我们表明重组R5111能够通过嵌合糖蛋白D与IL-13Rα2的相互作用进入并感染细胞，但该病毒保留了在表达天然病毒受体HveA或nectin-1的细胞中结合和复制的能力。在此，我们报道了一种重组病毒（R5141）的构建，该病毒只能在表达IL-13Rα2的细胞中进入并复制。重组R5141不依赖内吞作用来感染细胞。它不感染表达HveA或nectin-1受体的细胞，也不感染在感染前已暴露于可溶性IL-13的表达IL-13Rα2的细胞。此处描述的研究表明，单纯疱疹病毒的宿主范围可以通过基因操作进行改变，以特异性靶向癌细胞。
