Guayasamin Ryann C, Reynolds Tracy D, Wei Xin, Fujiwara Mai, Robek Michael D
Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA.
Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA Department of Infectious Diseases, Tangdu Hospital, Fourth Military Medical University, Xi'an, China.
J Virol. 2014 Sep;88(18):10909-17. doi: 10.1128/JVI.01910-14. Epub 2014 Jul 9.
Vesicular stomatitis virus (VSV) has been extensively studied as a vaccine vector and oncolytic agent. Nevertheless, safety concerns have limited its widespread use in humans. The type III lambda interferon (IFN-λ) family of cytokines shares common signaling pathways with the IFN-α/β family and thus evokes similar antiviral activities. However, IFN-λ signals through a distinct receptor complex that is expressed in a cell type-specific manner, which restricts its activity to epithelial barriers, particularly those corresponding to the respiratory and gastrointestinal tracts. In this study, we determined how IFN-λ expression from recombinant VSV would influence vector replication, spread, and immunogenicity. We demonstrate that IFN-λ expression severely attenuates VSV in cell culture. In vivo, IFN-λ limits VSV replication in the mouse lung after intranasal administration and reduces virus spread to other organs. Despite this attenuation, however, the vector retains its capacity to induce protective CD8 T cell and antibody responses after a single immunization. These findings demonstrate a novel method of viral vector attenuation that could be used in both vaccine and oncolytic virus applications.
Viruses such as VSV that are used as vaccine vectors can induce protective T cell and antibody responses after a single dose. Additionally, IFN-λ is a potent antiviral agent that has certain advantages for clinical use compared to IFN-α/β, such as fewer patient side effects. Here, we demonstrate that IFN-λ attenuates VSV replication and spread following intranasal virus delivery but does not reduce the ability of VSV to induce potent protective immune responses. These findings demonstrate that the type III IFN family may have widespread applicability for improving the safety and efficacy of viral vaccine and oncolytic vectors.
水泡性口炎病毒（VSV）作为疫苗载体和溶瘤剂已得到广泛研究。然而，安全问题限制了其在人类中的广泛应用。III型λ干扰素（IFN-λ）细胞因子家族与IFN-α/β家族共享共同的信号通路，因此引发类似的抗病毒活性。然而，IFN-λ通过以细胞类型特异性方式表达的独特受体复合物发出信号，这将其活性限制在上皮屏障，特别是与呼吸道和胃肠道相对应的屏障。在本研究中，我们确定了重组VSV表达的IFN-λ如何影响载体的复制、传播和免疫原性。我们证明，IFN-λ的表达在细胞培养中严重减弱VSV。在体内，鼻内给药后IFN-λ限制VSV在小鼠肺部的复制，并减少病毒传播到其他器官。然而，尽管有这种减弱，该载体在单次免疫后仍保留其诱导保护性CD8 T细胞和抗体反应的能力。这些发现证明了一种新的病毒载体减毒方法，可用于疫苗和溶瘤病毒应用。
用作疫苗载体的病毒如VSV在单次给药后可诱导保护性T细胞和抗体反应。此外，IFN-λ是一种有效的抗病毒剂，与IFN-α/β相比在临床使用中有某些优势，如患者副作用较少。在这里，我们证明鼻内病毒递送后IFN-λ减弱VSV的复制和传播，但不降低VSV诱导强效保护性免疫反应的能力。这些发现表明III型干扰素家族可能在提高病毒疫苗和溶瘤载体的安全性和有效性方面具有广泛的适用性。
