Studies on ZAP, a broad-spectrum alphavirus inhibitor

描述(由申请人提供)：被Togaviridae家族的病毒感染导致严重的全球发病率和死亡率。目前还没有针对感染该家族任何病毒的患者的具体治疗。甲型病毒属的病毒会引起从发烧、皮疹和关节炎到致命性脑炎的各种疾病。该属的几个成员已被确定为可能的生物恐怖主义病原体。我们的初步研究表明，大鼠锌指抗病毒蛋白(ZAP)最初被发现是一种抑制逆转录病毒复制的宿主蛋白，它有效地抑制了甲型病毒属多个成员的复制。辛德比斯病毒(SIND)、罗斯河病毒、塞姆利基森林病毒和委内瑞拉马脑炎病毒的复制都有不同程度的抑制。该项目的长期目标是利用病毒学、分子和细胞生物学方法阐明ZAP抑制甲型病毒复制的机制(S)。使用已经被广泛研究并被ZAP显著抑制的SIN的研究表明，在进入之后以及在传入的正链基因组RNA翻译时或之前，复制被阻止。本提案中概述的实验将确定ZAP水平和SIN复制之间的关系，并将研究ZAP阻止SIN RNA翻译的机制。我们将描述ZAP与SIN RNA之间的相互作用，以及ZAP与其他宿主或病毒因子之间的相互作用(如果有的话)。了解ZAP抑制甲型病毒复制的机制可能会导致开发新的治疗或预防甲型病毒感染疾病的药物。

DESCRIPTION (provided by applicant): Infection by viruses in the Togaviridae family causes significant worldwide morbidity and mortality. There is currently no specific treatment for patients infected with any virus from this family. Viruses in the Alphavirus genus cause diseases ranging from fever, rash and arthritis to fatal encephalitis. Several members of this genus have been identified as possible agents of bioterrorism. Our preliminary studies indicate that the rat zinc-finger antiviral protein (ZAP), which was originally discovered as a host protein that inhibits replication of retroviruses, potently inhibits replication of multiple members of the Alphavirus genus. Sindbis virus (SIN), Ross River virus, Semliki Forest virus and Venezuelan equine encephalitis virus replication were all inhibited to varying extents. The long-term objectives of this project are to elucidate, using virological, molecular and cell biological approaches, the mechanism(s) by which ZAP inhibits replication of alphaviruses. Investigations using SIN, which has been studied extensively and is dramatically inhibited by ZAP, show that replication is blocked after entry and at or before translation of the incoming plus strand genomic viral RNA. Experiments outlined in this proposal will determine the relationship between ZAP levels and SIN replication, and will investigate the mechanism by which ZAP blocks SIN RNA translation. We will characterize the interaction between ZAP and the SIN RNA, as well as the interaction, if any, between ZAP and other host or viral factors. Understanding the mechanism of ZAP's inhibition of alphavirus replication may lead to the development of new therapeutic or preventative agents for illness due to alphavirus infection.