Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut, USA.
J Virol. 2014 May;88(9):4932-42. doi: 10.1128/JVI.03508-13. Epub 2014 Feb 19.
Members of the genus Parvovirus are small, nonenveloped single-stranded DNA viruses that are nonpathogenic in humans but have potential utility as cancer therapeutics. Because the innate immune response to parvoviruses has received relatively little attention, we compared the response to parvoviruses to that of several other types of viruses in human cells. In normal human glia, fibroblasts, or melanocytes, vesicular stomatitis virus evoked robust beta interferon (IFN-β) responses. Cytomegalovirus, pseudorabies virus, and Sindbis virus all evoked a 2-log-unit or greater upregulation of IFN-β in glia; in contrast, LuIII and MVMp parvoviruses did not evoke a detectable IFN-β or interferon-stimulated gene (ISG; MX1, oligoadenylate synthetase [OAS], IFIT-1) response in the same cell types. The lack of response raised the question of whether parvoviral infection can be attenuated by IFN; interestingly, we found that IFN did not decrease parvovirus (MVMp, LuIII, and H-1) infectivity in normal human glia, fibroblasts, or melanocytes. The same was true in human cancers, including glioma, sarcoma, and melanoma. Similarly, IFN failed to attenuate transduction by the dependovirus vector adeno-associated virus type 2. Progeny production of parvoviruses was also unimpaired by IFN in both glioma and melanoma, whereas vesicular stomatitis virus replication was blocked. Sarcoma cells with upregulated IFN signaling that show high levels of resistance to other viruses showed strong infection by LuIII. Unlike many other oncolytic viruses, we found no evidence that impairment of innate immunity in cancer cells plays a role in the oncoselectivity of parvoviruses in human cells. Parvoviral resistance to the effects of IFN in cancer cells may constitute an advantage in the virotherapy of some tumors.
Understanding the interactions between oncolytic viruses and the innate immune system will facilitate employing these viruses as therapeutic agents in cancer patients. The cancer-selective nature of some oncolytic viruses is based on the impaired innate immunity of many cancer cells. The parvoviruses H-1, LuIII, and MVM target cancer cells; however, their relationship with the innate immune system is relatively uncharacterized. Surprisingly, we found that these parvoviruses do not evoke an interferon response in normal human fibroblasts, glia, or melanocytes. Furthermore, unlike most other types of virus, we found that parvovirus infectivity is unaffected by interferon treatment of human normal or tumor cells. Finally, parvoviral replication was unimpaired by interferon in four human tumor types, including those with residual interferon functionality. We conclude that deficits in the interferon antiviral response of cancer cells do not contribute to parvoviral oncoselectivity in human cells. The interferon-resistant phenotype of parvoviruses may give them an advantage over interferon-sensitive oncolytic viruses in tumors showing residual interferon functionality.
了解溶瘤病毒与先天免疫系统之间的相互作用将有助于将这些病毒作为治疗剂应用于癌症患者。一些溶瘤病毒的肿瘤选择性基于许多癌细胞先天免疫受损的特性。一些溶瘤病毒，如 H-1、LuIII 和 MVM，靶向癌细胞，但它们与先天免疫系统的关系相对未知。令人惊讶的是，我们发现这些细小病毒在正常人成纤维细胞、神经胶质细胞或黑素细胞中不会引发干扰素反应。此外，与大多数其他类型的病毒不同，我们发现干扰素处理正常人或肿瘤细胞不会影响细小病毒的感染性。最后，干扰素对包括仍具有干扰素功能的肿瘤在内的四种人类肿瘤类型的细小病毒复制没有影响。我们得出结论，癌细胞中干扰素抗病毒反应的缺陷不会导致细小病毒在人类细胞中的肿瘤选择性。与具有残留干扰素功能的肿瘤相比，细小病毒的干扰素抗性表型可能使它们比干扰素敏感的溶瘤病毒更具优势。
