HERPES SIMPLEX VIRUS ENTRY INTO CELLS OF NEURAL ORIGIN

单纯疱疹病毒（HSV）引起多种人类疾病，包括 唇疱疹，眼睛和生殖器感染，新生儿感染， 脑炎神经系统在发病机制中起着核心作用 关于HSV病毒的两种血清型，HSV-1（口服形式）和HSV-2（口服形式） 生殖器形式）在感觉器官内建立终身潜伏感染 神经节此外，神经系统是发病的主要目标 以及疱疹性脑炎和新生儿疱疹导致的死亡率。 神经元在HSV发病机制中的核心作用， 实验方法集中在HSV感染的这一方面。这 一项关于HSV进入神经源细胞的机制的提案 引发感染在11种病毒体编码的糖蛋白中， 包括gB、gD和gH-gL的复合物对于病毒进入是必需的。一 第五，gC虽然不是必需的，但对于促进初始 与细胞表面硫酸乙酰肝素蛋白聚糖结合的附着 （HSPG）。gD的一个主要功能是与特定的细胞相互作用， 受体。其中之一，称为疱疹病毒进入介体或HVEM，是一种 肿瘤坏死因子受体（TNFR）超家族成员， 膜蛋白，主要存在于T细胞和其他细胞上。 免疫系统最近，两个额外的介质，允许HSV进入 转移到其他不允许的细胞中。两个都是孤儿 受体与蛋白质的IG超家族，并且是 人脊髓灰质炎病毒受体（hPVR）。它们被称为人类脊髓灰质炎病毒 相关受体1和2，或hPRR 1和hPRR 2。我们发现可溶性hPRR 1 可饱和并特异性地结合可溶形式的gD和 这种相互作用不需要其他病毒体糖蛋白。 此外，hPRR 1的结合依赖于gD构象，但不依赖于gD构象。 涉及gD的N-聚糖。因此，像HVEM一样，hPRR 1满足我们的要求。 对真正的gD受体特性的期望。我们假设 hPRR 1是神经源细胞上HSV的主要受体。测试 这一假设，提出了两个具体的目标：1）表征 纯化形式的gD和hPRR 1之间的相互作用;和2）检查 人神经系统病毒、细胞和组织中的gD-受体相互作用 起源

Herpes simplex viruses (HSVs) cause a variety of human diseases, including cold sores, eye and genital infections, neonatal infections and encephalitis. The nervous system plays a central role in the pathogenesis of HSV. Both serotypes of the virus, HSV-1 (the oral form) and HSV-2 (the genital form) establish life-long latent infections within sensory ganglia. In addition, the nervous system is the major target of morbidity and mortality resulting from herpetic encephalitis and neonatal herpes. The central role of the neuron in the pathogenesis of HSV argues for experimental approaches that focus on this aspect of HSV infection. This proposal concerns the mechanism by which HSV enter cells of neural origin to initiate infection. Of the eleven virion-encoded glycoproteins, four, including gB, gD and a complex of gH-gL, are essential for virus entry. A fifth, gC though not essential, is important for facilitating initial attachment by binding to cell surface heparan sulfate proteoglycans (HSPG). A major function of gD is to interact with specific cellular receptors. One of these, called herpes virus entry mediator or HVEM, is a member of the tumor necrosis factor receptor (TNFR) superfamily of membrane proteins and is found primarily on T cells and other cells of the immune system. Recently, two additional mediators that allow HSV entry into otherwise non-permissive cells have been identified. Both are orphan receptors with the Ig superfamily of proteins and are homologues of the human polio-virus receptor (hPVR). They have been termed human polio-virus related receptors 1 and 2, or hPRR1 and hPRR2. We found that soluble hPRR1 binds saturably and specifically to soluble forms of gD and to gD in virions No other virion glycoproteins are needed for this interaction. Furthermore, binding of hPRR1 depends on gD conformation but does not involved the N-glycans of gD. Thus, like HVEM, hPRR1 satisfies our expectations for the properties of a bona-fide gD-receptor. We hypothesize that hPRR1 is a major receptor for HSV on cells of neural origin. To test this hypothesis, two specific aims are proposed: 1) to characterize the interaction between purified forms of gD and hPRR1; and 2) to examine the gD-receptor interaction in viruses, cells, and tissues of human neural origin.