CONTROL OF ALPHAVIRUS REPLICATION IN THE NERVOUS SYSTEM

描述：辛德毕斯病毒（SV）是一种感染神经元的甲病毒， 导致小鼠急性脑脊髓炎。中枢非致死性SV感染 断奶小鼠的神经系统（CNS）引发了特征明确的免疫 反应，并提供了一个模型系统，用于研究机制，其中病毒是 清除神经细胞严重联合免疫缺陷（SCID）小鼠 不能清除病毒，这些小鼠发展为持续感染。申请人 被动转移实验表明，抗体（Ab）是主要的 感染性病毒从CNS清除的机制。Ab介导 细胞内病毒复制的控制不依赖于补体， 白细胞，是非细胞溶解性的，需要E2糖蛋白的交联 在受感染细胞的表面。SV复制的下调是 与改善的Na+K+ ATP酶依赖的阳离子通量控制有关， 导致宿主蛋白质合成的恢复和对1型的应答 干扰素（IFN）。在小鼠中，这种控制病毒的非细胞毒性机制 复制导致病毒RNA在CNS中的持续存在， CNS中B细胞产生抗病毒抗体。在当前应用中， 申请人建议确定抗体控制 细胞内病毒在体内和体外的复制以及IFN在 这一进程通过以下具体目标：（1）确定所需 抗体特异性和细胞定位 细胞内SV复制;（2）确定抗体 SV的E2糖蛋白恢复Na+K+ ATP酶功能，并控制 细胞内病毒复制;（3）确定 用于体内控制SV的抗体、干扰素和T细胞细胞因子 复制的

DESCRIPTION: Sindbis virus (SV) is an alphavirus that infects neurons and causes acute encephalomyelitis in mice. Non-fatal SV infection of the central nervous system (CNS) of weanling mice elicits a well-characterized immune response and provides a model system for studying mechanisms by which virus is cleared from neural cells. Mice with severe combined immunodeficiency (SCID) cannot clear virus and these mice develop persistent infection. The applicant has shown by passive transfer experiments that antibody (Ab) is the primary mechanism by which infectious virus is cleared from the CNS. Ab-mediated control of intracellular virus replication is independent of complement and leukocytes, is noncytolytic and requires cross-linking of the E2 glycoprotein on the surface of the infected cell. Downregulation of SV replication is associated with improved Na+K+ATPase-dependent control of cation flux and results in restoration of host protein synthesis and response to type 1 interferons (IFNs). In mice this noncytotoxic mechanism for control of virus replication results in persistence of viral RNA in the CNS and long-term local production of antiviral Ab by B cells in the CNS. In the current application, the applicant proposes to determine the mechanism by which Ab controls intracellular virus replication in vivo and in vitro and the role of IFN in this process through the following specific aims: (1) To define the required specificity and cellular localization of antibody for effective control of intracellular SV replication; (2) To determine the mechanism by which antibody to the E2 glycoprotein of SV restores Na+K+ATPase function and controls intracellular virus replication; (3) To determine the relative roles of antibody, interferon and T cell cytokines for in vivo control of SV replication.