LENTIVIRUS-HOST INTERACTIONS DURING ASSEMBLY AND RELEASE

描述：这项建议的总体目标是提高我们的理解 控制人类和猫科动物装配和退出的分子机制 免疫缺陷病毒(分别为HIV-1和FIV)。虽然内部 逆转录病毒的结构蛋白，即所谓的Gag蛋白，可以形成 在没有其他病毒成分的情况下，被膜包裹的颗粒， 病毒包膜糖蛋白(Env)与控制地点和方式有关 许多病毒是从受感染的细胞中释放出来的。他们在病毒式生活中的地位 因此，循环是关键的，不仅因为它们控制了病毒的附着和进入 还因为它们调节了新组装的粒子到底从哪里出来 在病毒复制周期的后期从细胞中分离出来。在空间上 限制、定向释放逆转录病毒可能特别重要。 当感染细胞接触潜在的靶细胞时，例如当免疫缺陷时 病毒跨越上皮屏障或从外围迁移 淋巴器官和中枢神经系统。病毒的调控 因此，出口很可能会对病毒的传播过程产生重大影响。 播散与发病机制。因此，它也是潜在的目标 治疗性干预。 我们建议对慢病毒(HIV-1；FIV)的后期事件进行分子解剖 使用细胞生物学、生化和病毒学方法进行复制循环。 我们的重点是Env在病毒组装和释放过程中的作用，我们将 重视研究Env与宿主细胞蛋白的相互作用 带着病毒般的恶作剧。本提案的具体目的是：1)进一步明确 慢病毒环境(HIV-1；FIV)中与其关联所必需的信号 与细胞运输机制的蛋白质，从而为 环境的后高尔基路径特征；2)检验假设 环境病毒到特定亚细胞位置的运输，如在特定的 目标1，负责定向病毒释放并测试是否错误定位 粒子脱落会损害病毒的传播。对……的彻底评估 控制病毒释放不对称性的病毒-宿主相互作用将 也为进一步研究提供必要的基础，旨在 确定与病毒传播和病毒传播有关的其他环境晚期功能 致病性。

DESCRIPTION: The overall goal of this proposal is to improve our understanding of the molecular mechanisms which control assembly and exit of human and feline immunodeficiency viruses (HIV-1 and FIV, respectively). Though the internal structural proteins of retroviruses, the so-called Gag proteins, can form membrane-enveloped particles in the absence of other viral components, the viral envelope glycoproteins (Env) are implicated in controlling where and how much virus is released from infected cells. Their position in the viral life cycle is thus pivotal not only because they control virus attachment and entry but also because they regulate where exactly newly assembled particles exit from cells during the late phase of the viral replication cycle. Spatially restricted, directional release of retrovirus may be particularly important when infected cells contact potential target cells, e.g. when immunodeficiency viruses cross epithelial barriers or during their migration from the periphery to lymphoid organs and the central nervous system. The regulation of virus egress is thus likely to influence substantially the course of virus dissemination and pathogenesis. As such it also presents a potential target for therapeutic intervention. We propose a molecular dissection of late events of the lentiviral (HIV-1; FIV) replication cycle using cell-biological, biochemical and virological methods. Our focus is on the role of Env during viral assembly and release and we will put emphasis on studying the interactions of Env with host-cell proteins and with viral Gag. The specific aims ofthis proposal are 1) to further define signals in lentiviral Env (HIV-1; FIV) that are necessary for its association with proteins of the cellular trafficking machinery and thus for the characteristics of the post-Golgi routing of Env; 2) to test the hypothesis that the transport of Env to specific subcellular sites, as defined in Specific Aim 1, is responsible for directional virus release and to test if mistargeting of particle shedding impairs virus propagation. A thorough assessment of virus-host interactions, which control the asymmetry of virus release, will also provide the necessary groundwork for further studies aiming at the identification of additional Env late functions implicated in virus spread and pathogenicity.