Spread of HSV-1 mediated by the gD receptor nectin-1

描述(申请人提供)：单纯疱疹病毒(HSV)感染上皮细胞通常会导致病毒在上皮内扩散，并对神经元建立潜伏感染。重新激活会导致病毒从神经元传播回上皮细胞。病毒可以在上皮中破坏性地传播，通常是在中和抗体存在的情况下， 导致形成一种特征性病变。HSV通过三种方式从感染细胞传播到未感染细胞。首先，细胞外病毒与相邻细胞上的细胞表面受体结合，并通过病毒和细胞膜的融合进入(病毒进入)。第二，感染细胞表面的病毒糖蛋白诱导与邻近的未感染细胞融合。 导致巨大的多核细胞被称为合胞体(细胞融合)。第三种形式的病毒传播发生在连续的细胞之间，存在中和抗体，没有合胞体形成(细胞间传播)。细胞表面的gD受体，如Nectin-1，是所有三种传播形式所必需的。这些研究的长期目标是描述 所有三种形式的依赖于Nectin-1的病毒传播的机制。我们假设，对于这三种活动(因此机制)至关重要的Nectin-1的结构特征可能不同，特别是对细胞-细胞扩散来说。为了验证这一假设，我们将确定Nectin-1的结构域，这些结构域对细胞融合和细胞间传播非常重要。我们会 通过研究黏附连接蛋白在上皮细胞中有效的细胞-细胞扩散的功能要求，进一步表征细胞-细胞扩散的机制。这些研究的结果，当与以前关于病毒进入的工作进行比较和对比时，将阐明在病毒传播过程中Nectin-1在细胞膜上介导的事件。这些结果是重要的 用于描述病毒在上皮细胞中传播的特征，也可能对于描述病毒向神经元的传播和神经元间传播的特征很重要。这些研究的结果将有助于理解病毒在人类和动物疱疹病毒中的传播。

DESCRIPTION (provided by applicant): Herpes simplex virus (HSV) infection of epithelial cells often leads to spread of virus within the epithelium and to neurons for the establishment of a latent infection. Reactivation results in spread of virus from neurons back to epithelial cells. The virus can spread destructively in an epithelium, often in the presence of neutralizing antibody, resulting in the formation of a characteristic lesion. HSV spreads from an infected cell to an uninfected cell in three ways. First, extracellular virus binds cell-surface receptors on the adjacent cell and enters by fusion of the viral and cellular membranes (viral entry). Second, viral glycoproteins on the surface of the infected cell induce fusion with adjacent uninfected cells resulting in giant-multinucleated cells called syncytia (cell fusion). The third form of viral spread occurs between contiguous cells in the presence of neutralizing antibody and absence of syncytium formation (cell-cell spread). A cell-surface gD receptor, such as nectin-1, is required for all three forms of spread. The long term objective of these studies is to characterize the mechanisms of all three forms of nectin-1-dependent viral spread. We hypothesize that the structural features of nectin-1 that are critical for these three activities (and therefore the mechanisms) may differ, particularly for cell-cell spread. To test this hypothesis, we will identify domains of nectin-1 that are important for cell fusion and cell-cell spread. We will further characterize the mechanism of cell-cell spread by examining the functional requirements of adherens-junction proteins for efficient cell-cell spread in epithelial cells. The results of these studies, when compared and contrasted with previous work in viral entry, will elucidate nectin-1-mediated events at the cell membrane during viral spread. These results are important for the characterization of viral spread in an epithelium and may also be important for the characterization of spread of virus to neurons and interneuronal spread. Results from these studies will contribute to the understanding of viral spread in human and animal herpesviruses.