Deletion of immune evasion genes provides an effective vaccine design for tumor-associated herpesviruses.
Deletion of immune evasion genes provides an effective vaccine design for tumor-associated herpesviruses.
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DOI：
10.1038/s41541-020-00251-x
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发表时间：
2020-11-05
期刊：
影响因子：
9.2
通讯作者：
Wu TT
中科院分区：
文献类型：
--
作者：
Brar G;Farhat NA;Sukhina A;Lam AK;Kim YH;Hsu T;Tong L;Lin WW;Ware CF;Blackman MA;Sun R;Wu TT
以减毒活病毒为基础的疫苗通常会引起广泛的、多方面的免疫反应。然而，它们通常也会牺牲免疫原性来衰减。由于存在大量的免疫逃避基因和潜伏期，研制有效的疱疹病毒疫苗尤为困难。为了克服衰减的限制，我们开发了一种合理的疱疹病毒疫苗，其中删除了病毒免疫逃避基因，以增强免疫原性，同时获得安全性。为了验证这种疫苗策略，我们利用小鼠γ-疱疹病毒-68 （MHV-68）作为癌症相关的人类γ-疱疹病毒、爱泼斯坦-巴尔病毒和卡波西肉瘤相关疱疹病毒的概念验证模型。我们通过靶向灭活I型干扰素（IFN-I）途径的病毒拮抗剂和删除导致持续感染的潜伏期位点，设计了重组MHV-68病毒。这种重组病毒是高度减毒的，在免疫能力强的宿主中没有可测量的复制能力、潜伏期或持久性。它刺激强大的先天免疫，分化病毒特异性记忆T细胞，并引起中和抗体。单次疫苗接种可提供持久的保护，在疫苗接种后至少6个月内阻断野生型MHV-68攻击后潜伏期的建立。这些结果为通过消除潜伏期和病原体的关键免疫逃避机制有效接种癌症相关疱疹病毒提供了框架。
Vaccines based on live attenuated viruses often induce broad, multifaceted immune responses. However, they also usually sacrifice immunogenicity for attenuation. It is particularly difficult to elicit an effective vaccine for herpesviruses due to an armament of immune evasion genes and a latent phase. Here, to overcome the limitation of attenuation, we developed a rational herpesvirus vaccine in which viral immune evasion genes were deleted to enhance immunogenicity while also attaining safety. To test this vaccine strategy, we utilized murine gammaherpesvirus-68 (MHV-68) as a proof-of-concept model for the cancer-associated human γ-herpesviruses, Epstein–Barr virus and Kaposi sarcoma-associated herpesvirus. We engineered a recombinant MHV-68 virus by targeted inactivation of viral antagonists of type I interferon (IFN-I) pathway and deletion of the latency locus responsible for persistent infection. This recombinant virus is highly attenuated with no measurable capacity for replication, latency, or persistence in immunocompetent hosts. It stimulates robust innate immunity, differentiates virus-specific memory T cells, and elicits neutralizing antibodies. A single vaccination affords durable protection that blocks the establishment of latency following challenge with the wild type MHV-68 for at least six months post-vaccination. These results provide a framework for effective vaccination against cancer-associated herpesviruses through the elimination of latency and key immune evasion mechanisms from the pathogen.
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