Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy.
Vaccine. 2011 May 23;29(23):3935-44. doi: 10.1016/j.vaccine.2011.03.092. Epub 2011 Apr 8.
Human gammaherpesviruses such as Epstein-Barr virus (EBV) cause lifelong infections and associated diseases, by virtue of their ability to establish latent infection. Many studies performed in the past years in murine herpesvirus 68 (MHV-68) model of infection suggested that the limited immunity generated against isolated viral components by subunit vaccines cannot counteract the multiple immune evasion strategies operated by gammaherpesviruses. Indeed, a significant inhibition of long-term latency establishment could be observed in mice vaccinated with strains of genetically modified MHV-68 defective in reactivation or establishment of latency. In this study, we focused on the effects of interferon-α (IFN-α) on both the lytic and latent phase of MHV-68 infection, as exerted by the constitutive release of IFN-α1 by a clone of MHV-68 genetically modified to produce this cytokine (MHV-68mIFNα1). Although the MHV-68mIFNα1 recombinant virus exhibited in vitro replication features indistinguishable from those of the wild type MHV-68, its pathological properties were severely attenuated in vivo in immunocompetent mice and not in mice rendered genetically unresponsive to type I IFN, suggesting that a stronger immune response was primed in the presence of the cytokine. Notably, MHV-68mIFNα1 attenuation did not result in a reduced level of long-term spleen latency establishment. These results prompted us to evaluate the efficacy of MHV-68mIFNα1 in a prophylactic vaccination regimen aimed at inhibiting the symptoms of acute virus infection and the establishment of long-term latency after MHV-68 challenge. Our results show that mice vaccinated with MHV-68mIFNα1, administered as a live-attenuated or partially inactivated (by Psoralen and UV treatment) vaccine, were protected against the challenge with wt MHV-68 from all phases of infection. The ability of MHV-68mIFNα1 to produce IFN-α at the site of the infection, thus efficiently stimulating the immune system in case of virus reactivation from latency, makes this recombinant virus a safer live-attenuated vaccine as compared to the previously reported latency-deficient clones.
人类γ疱疹病毒，如 Epstein-Barr 病毒（EBV），通过建立潜伏感染而导致终身感染和相关疾病。过去几年在鼠γ疱疹病毒 68（MHV-68）感染模型中进行的许多研究表明，亚单位疫苗针对分离的病毒成分产生的有限免疫力无法对抗γ疱疹病毒的多种免疫逃避策略。事实上，在用缺失再激活或潜伏建立能力的遗传修饰 MHV-68 株疫苗接种的小鼠中，可以观察到对长期潜伏建立的显著抑制。在这项研究中，我们专注于干扰素-α（IFN-α）对 MHV-68 感染的裂解和潜伏阶段的影响，这是由遗传修饰产生这种细胞因子的 MHV-68 克隆（MHV-68mIFNα1）组成型释放 IFN-α1 引起的。尽管 MHV-68mIFNα1 重组病毒在体外复制特征与野生型 MHV-68 无法区分，但在免疫功能正常的小鼠中，其病理特性在体内严重减弱，而在对 I 型 IFN 无遗传反应性的小鼠中则没有，这表明在存在细胞因子的情况下，引发了更强的免疫反应。值得注意的是，MHV-68mIFNα1 的衰减并没有导致长期脾脏潜伏建立水平降低。这些结果促使我们评估 MHV-68mIFNα1 在预防性疫苗接种方案中的功效，该方案旨在抑制 MHV-68 感染后急性病毒感染的症状和长期潜伏的建立。我们的结果表明，用 MHV-68mIFNα1 疫苗接种的小鼠，无论是作为活减毒疫苗还是部分灭活（用补骨脂素和紫外线处理）疫苗接种，都能抵抗来自感染所有阶段的 wt MHV-68 的挑战。MHV-68mIFNα1 在感染部位产生 IFN-α 的能力，从而在潜伏病毒重新激活时有效地刺激免疫系统，使这种重组病毒成为比以前报道的潜伏缺陷克隆更安全的活减毒疫苗。
