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

描述（由申请人提供）：上皮细胞的单纯疱疹病毒（HSV）感染通常导致病毒在上皮内扩散并扩散至神经元，从而建立潜伏感染。再活化导致病毒从神经元扩散回上皮细胞。病毒可在上皮细胞中破坏性传播，通常在中和抗体存在的情况下， 导致特征性损伤的形成。HSV通过三种方式从受感染的细胞传播到未受感染的细胞。首先，细胞外病毒结合相邻细胞上的细胞表面受体，并通过病毒和细胞膜的融合进入（病毒进入）。其次，感染细胞表面的病毒糖蛋白诱导与邻近未感染细胞的融合 导致称为合胞体（细胞融合）的巨大多核细胞。第三种形式的病毒传播发生在存在中和抗体且不存在合胞体形成的相邻细胞之间（细胞-细胞传播）。细胞表面gD受体，如nectin-1，是所有三种形式的传播所必需的。这些研究的长期目标是表征 所有三种形式的nectin-1依赖性病毒传播的机制。我们假设，nectin-1的结构特征，这是至关重要的这三个活动（因此机制）可能会有所不同，特别是细胞间的传播。为了验证这一假设，我们将确定的结构域的nectin-1是重要的细胞融合和细胞-细胞传播。我们将 通过检查粘附蛋白-连接蛋白在上皮细胞中有效细胞-细胞扩散的功能需求，进一步表征细胞-细胞扩散的机制。这些研究的结果，当比较和对比以前的工作中的病毒进入，将阐明连接蛋白-1介导的事件在细胞膜病毒传播过程中。这些结果是重要 用于表征病毒在上皮中的传播，并且对于表征病毒向神经元的传播和神经元间的传播也可能是重要的。这些研究的结果将有助于了解人类和动物疱疹病毒的病毒传播。

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.