HERPES SIMPLEX VIRUS ENTRY INTO CELLS OF NEURAL ORIGIN

单纯疱疹病毒(HSV)会导致多种人类疾病，包括 唇疱疹、眼睛和生殖器感染、新生儿感染和 脑炎。神经系统在发病机制中起核心作用。 单纯疱疹病毒。HSV-1(口服形式)和HSV-2(口服形式)这两种血清类型的病毒 生殖器形式)在感官上建立终生潜伏感染 神经节。此外，神经系统是发病的主要目标。 以及由疱疹病毒性脑炎和新生儿疱疹引起的死亡。 神经元在单纯疱疹病毒发病机制中的中心作用 专注于HSV感染这一方面的实验方法。这 建议涉及HSV进入神经源性细胞的机制 以引发感染。在11种病毒粒子编码的糖蛋白中，有4种， 包括gB、gD和Gh-gl的复合体，是病毒入侵所必需的。一个 第五，GC虽然不是必需的，但对于促进初始 通过与细胞表面硫酸乙酰肝素蛋白多糖结合而附着 (HSPG)。GD的一个主要功能是与特定的细胞相互作用 感受器。其中一种被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，又增加了两个允许HSV进入的中介 在其他方面是不允许的牢房已经被识别。两人都是孤儿 受体与免疫球蛋白超家族蛋白同源 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hPRR1和hPRR2。我们发现可溶性hPRR1 饱和地和特异地结合到可溶性的Gd和Gd 病毒粒子这种相互作用不需要其他病毒粒子糖蛋白。 此外，hPRR1的结合依赖于gD构象，但不依赖于 涉及GD的N-糖链。因此，像hvem一样，hPRR1满足我们的 对真正的Gd受体特性的期望。我们假设 HPRR1是神经源性细胞上HSV的主要受体。为了测试 在这一假设中，提出了两个具体的目标：1)表征 纯化形式的GD与hPRR1之间的相互作用；以及2)检测 人神经病毒、细胞和组织中Gd受体的相互作用 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.