Natural History and Pathogenesis of WNV in Viremic Dono*

描述（由申请人提供）：直到最近，大多数被确定为西尼罗河病毒感染的人都出现了西尼罗河病毒热或脑膜脑炎的症状。当症状出现时，病毒血症通常已经清除，免疫反应已经形成，这使得准确描述感染的临床谱或研究病毒与免疫系统之间的相互作用变得困难。2003年中期，美国开始使用核酸扩增试验（NAT）对献血者进行西尼罗河病毒RNA筛查，这种情况发生了巨大变化。NAT筛选将允许表征急性病毒血症的动力学和免疫反应的时间过程在原发性西尼罗河病毒感染。对病毒血症、血清转化前供者的前瞻性登记和详细的临床、病毒学和免疫学研究将更好地确定感染的自然史以及与病毒血症和各种西尼罗河病毒疾病综合征控制相关的病毒和宿主因素。我们将从美国红十字会（ARC）和血液系统（BSI）血库网络检测到的一组独特的病毒血症个体中提取样本，这两家血库共收集了美国约60%的血液供应。ARC和BSI的医务人员将进行面谈（与疾病控制与预防中心合作制定），以确定西尼罗河病毒症状复合物的发展速度和严重程度。一组出现严重症状感染的病毒供体和匹配的无症状对照者将被纳入一项亚研究。我们将对频繁的序列样本进行病毒学和免疫学分析，以表征原发性病毒血症的动力学和西尼罗河病毒特异性IgM、IgA、IgG和斑块中和抗体血清转化的时间过程。T细胞反应的详细研究，包括动力学和抗原特异性，以及细胞因子扰动将在相同的情况下进行。因此，这些研究的发现将解决关键的血液安全问题，并通过确定与病毒血症控制相关的病毒和体液免疫参数，有助于我们了解西尼罗河病毒感染的自然历史和发病机制。

Description (provided by applicant): Until recently, most humans identified with WNV infection presented with symptoms of WNV fever or meningoencephalitis. By the time symptoms appear, viremia has typically cleared and immune responses evolved, making it difficult to accurately characterize the clinical spectrum of infection or study the interplay between the virus and the immune system. This situation changed dramatically when WNV RNA screening of blood donors using nucleic acid amplification tests (NAT) was implemented in the U.S. in mid-2003. NAT screening will allow characterization of the dynamics of acute viremia and time course of immune responses in primary WNV infection. Prospective enrollment of viremic, pre-seroconversion donors and detailed clinical, virologic and immunologic studies will better define the natural history of infection and the viral and host factors that correlate with control of viremia and varied WNV disease syndromes. We will draw our samples from a unique cohort of viremic individuals detected by the American Red Cross (ARC) and Blood Systems (BSI) networks of blood banks, which together collect approximately 60% of the U.S. blood supply. Medical staff at ARC and BSI will administer interviews (developed in collaboration with CDC) to ascertain the rates of development and severity of WNV-symptom complexes. A subset of viremic donors who develop severe symptomatic infections and matched asymptomatic controls, will be enrolled into a substudy. We will perform virologic and immunologic analyses of frequent sequential samples to characterize the kinetics of primary viremia and the time course of WNV-specific IgM, IgA, IgG and plaque neutralizing antibody seroconversion. Detailed studies of T cell responses, including kinetics and antigen specificity, and of cytokine perturbations will be carried out on the same cases. The findings from these studies will therefore address key blood safety issues and contribute to our understanding of the natural history and pathogenesis of WNV infection by identifying viral and humoral immune parameters that correlate with control of viremia.