University of Kansas Medical Center, Department of Microbiology, Molecular Genetics, and Immunology, Kansas City, Kansas, USA.
University of Kansas Medical Center, Department of Microbiology, Molecular Genetics, and Immunology, Kansas City, Kansas, USA
J Virol. 2019 Jan 4;93(2). doi: 10.1128/JVI.01850-18. Print 2019 Jan 15.
Herpes simplex virus 1 (HSV-1) infections afflict more than 80% of the population worldwide. The virus primarily infects mucoepithelial cells and establishes latent reservoirs in neurons in sensory ganglia. Frequent reactivation has been linked to severe diseases, especially in immunocompromised individuals. Earlier, we reported that viral and host factors are packaged in extracellular vesicles (EVs) and delivered to uninfected cells, where they activate antiviral responses and restrict virus infection. Here, we interrogated the effect of HSV-1 infection on EV biogenesis. We found that HSV-1 infection causes a decrease in the amount of intracellular CD63 protein with a concomitant increase in extracellular CD63. This observation correlates with our previous finding that infected cells release more CD63-positive EVs than uninfected cells. The stimulation of CD63 exocytosis requires virus replication. CD63 is a member of the tetraspanin family of proteins that traffics between the plasma membrane and endosomal compartments and has a role in sorting cargo into the EVs. Previously, we reported that in cells depleted of CD63, HSV-1 virus yields increased, and here we provide data showing that in cells overexpressing CD63, HSV-1 virus yields decreased. Taken together, our data indicate that CD63 negatively impacts HSV-1 infection and that the CD63-positive EVs could control the dissemination of the virus in the host. Perhaps EV release by HSV-1-infected cells is a mechanism that controls virus dissemination. Intercellular communication, especially in neurons, largely relies on EVs, and modulation of EVs is known to impact physiological processes. Here, we present evidence that HSV-1 infection causes major alterations in the biogenesis of EVs, including an increase in their number and an increase in the CD63-positive population of EVs. These alterations result in an enrichment of the milieu of infection with EVs carrying signatures from infected cells. In addition to changes in the origin and type, EVs released by infected cells have differences in cargo, as they carry viral and host factors determined by the virus. The tetraspanin CD63 negatively impacts the infection, as demonstrated by CD63-knockdown and overexpression assays. A proposed mechanism involves the activation of antiviral responses in cells receiving CD63-positive EVs released by infected cells. Overall, HSV-1 causes major alterations in EVs that could contribute to HSV-1 persistence and pathogenesis.
单纯疱疹病毒 1（HSV-1）感染影响全球超过 80%的人口。该病毒主要感染黏膜上皮细胞，并在感觉神经节的神经元中建立潜伏储库。频繁的再激活与严重疾病有关，尤其是在免疫功能低下的个体中。早些时候，我们报道了病毒和宿主因素被包裹在细胞外囊泡（EVs）中，并递送到未感染的细胞中，在那里它们激活抗病毒反应并限制病毒感染。在这里，我们研究了 HSV-1 感染对 EV 生物发生的影响。我们发现 HSV-1 感染导致细胞内 CD63 蛋白的含量减少，同时细胞外 CD63 增加。这一观察结果与我们之前的发现一致，即感染细胞释放的 CD63 阳性 EV 多于未感染细胞。CD63 外排的刺激需要病毒复制。CD63 是四跨膜蛋白家族的成员，在质膜和内体隔室之间运输，并在将货物分拣到 EV 中起作用。之前，我们报道了在耗尽 CD63 的细胞中，HSV-1 病毒产量增加，在这里我们提供的数据表明，在过表达 CD63 的细胞中，HSV-1 病毒产量减少。总之，我们的数据表明 CD63 对 HSV-1 感染有负面影响，而 CD63 阳性 EV 可能控制病毒在宿主中的传播。也许 HSV-1 感染细胞释放 EV 是一种控制病毒传播的机制。细胞间通讯，尤其是在神经元中，在很大程度上依赖于 EVs，而 EVs 的调节已知会影响生理过程。在这里，我们提供的证据表明，HSV-1 感染导致 EV 生物发生的重大改变，包括数量增加和 CD63 阳性 EV 群体增加。这些改变导致感染环境中富含携带感染细胞特征的 EV。除了起源和类型的变化外，感染细胞释放的 EV 在货物方面也存在差异，因为它们携带由病毒决定的病毒和宿主因子。四跨膜蛋白 CD63 通过 CD63 敲低和过表达测定证明对感染有负面影响。提出的机制涉及到在接收由感染细胞释放的 CD63 阳性 EV 的细胞中激活抗病毒反应。总体而言，HSV-1 导致 EV 的重大改变，这可能有助于 HSV-1 的持续存在和发病机制。
