Evolution and mechanism of restriction of herpesviruses by MxB

项目总结/摘要 疱疹病毒在世界范围内对人类健康造成巨大负担。为了应对这些感染， 在其它病原体中，宿主细胞表达数千个干扰素刺激的基因。一个这样的基因编码 一种粘液病毒抗性蛋白B（Mx B），有效限制包括单纯疱疹病毒在内的几种疱疹病毒 病毒1（HSV-1）、单纯疱疹病毒2（HSV-2）和巨细胞病毒（CMV）。MxB一直在经历快速的 灵长类动物的进化，反映在积极选择的遗传特征中，表明MxB一直是 数百万年来一直在与病毒进行军备竞赛。有趣的是，与人类MxB不同，来自人类的MxB等位基因 几种非人灵长类动物不抑制HSV-1复制。相比之下，所有测试的直系同源物都保留了抗病毒活性。 抗CMV活性。这些结果表明，人MxB，而非非人灵长类直系同源物，包括 与黑猩猩基因密切相关的基因，已经进化为限制HSV-1。这种情况似乎是一个罕见的例子， 宿主方在与病毒的进化军备竞赛中"获胜"。为了剖析MxB利用的机制 为了限制HSV-1，目标1中的研究将确定特定残基的作用，这些残基是必要的，足以 解释人类和黑猩猩MxB同源基因的不同限制性表型。旨在识别 作为MxB靶点的病毒因子，以及可能需要的宿主辅因子， 邻位连接测定结合质谱法。根据观察，HSV-2病毒株 在它们对人类和黑猩猩MxB敏感性方面，Aim2将鉴定哪些其他灵长类MxB直系同源物限制 这将有助于阐明表型发展的进化轨迹。 此外，由于人MxB仅限制HSV-2毒株的一个子集，因此序列差异的分析 将有助于鉴定MxB敏感性的病毒决定簇。总之，这一提议将 揭示了介导MxB和单纯疱疹病毒之间军备竞赛的关键因素，并将有助于 阐明MxB抗疱疹病毒的作用机制。

PROJECT SUMMARY/ABSTRACT Herpesviruses cause a substantial worldwide burden on human health. In response to infections by these and other pathogens, host cells express thousands of interferon-stimulated genes. One such gene encodes the myxovirus resistance protein B (MxB) that potently restricts several herpesviruses, including herpes simplex virus 1 (HSV-1), herpes simplex virus 2 (HSV-2), and cytomegalovirus (CMV). MxB has been undergoing rapid evolution in primates, as reflected in genetic signatures of positive selection, suggesting that MxB has been engaged in arms races with viruses over millions of years. Intriguingly, unlike human MxB, the MxB alleles from several non-human primates do not inhibit HSV-1 replication. In contrast, all tested orthologs retain antiviral activity against CMV. These results suggest that human MxB, but not non-human primate orthologs, including the closely related chimpanzee gene, has evolved to restrict HSV-1. This scenario appears to be a rare example of the host side “winning” during an evolutionary arms race with a virus. To dissect the mechanism MxB utilizes to restrict HSV-1, studies in Aim 1 will define the role of specific residues that are necessary and sufficient to explain differing restrictive phenotypes of human and chimpanzee MxB orthologs. Experiments aiming to identify viral factors that are the targets of MxB, as well as which host co-factors are potentially required, will employ proximity ligation assays coupled with mass spectrometry. Building on the observation that HSV-2 strains vary in their sensitivity to human and chimpanzee MxB, Aim 2 will identify which other primate MxB orthologs restrict which strains of HSV-2, which will help elucidate the evolutionary trajectory of the development of the phenotype. Additionally, because human MxB restricts only a subset of HSV-2 strains, analyses of sequence differences among the strains will aid in the identification of viral determinants of MxB sensitivity. Together, this proposal will reveal the critical factors mediating the arms races between MxB and herpes simplex viruses and will aid in elucidating the anti-herpesvirus mechanism of MxB.