Studies on the Epidemiology of H5N1 Influenza Evolution

描述(申请人提供)：高致病性禽流感病毒H5N1构成令人衰弱的大流行威胁。虽然预防性疫苗正在开发中，但为逃避免疫反应而进行的病毒进化仍然存在问题。因此，我的长期目标是了解这种病毒在选择性免疫压力下的抗原进化和分子流行病学，并深入了解潜在大流行毒株的起源和出现。中心假设是病毒逃逸突变体受到与中和抗体的特定相互作用的限制，这些突变体必须沿着确定的、显性的和可复制的进化路线进化才能逃离免疫压力。这一假设部分是基于对最近在人类人群中暴发的H5N1病毒的流行病学分析所观察到的结果。血凝素(HA)中的某些氨基酸变化参与了受体结合，在人类中比在禽类分离株中更常见，表明这些病毒在抗原性上是不同的。这种积极的选择可能是由于特定的免疫压力以及病毒适应人类宿主的过程。我将使用人类抗HA单抗来验证这一假设，以确定H5N1病毒在选择性免疫压力下的进化途径。此外，我还将把具体的逃生途径与流感感染的临床结果联系起来。具体地说，我提出了以下具体目标：1)鉴定一组中和和交叉中和抗H5抗体的表位及其作用机制。2)鉴定由这些抗体诱导的病毒逃逸突变体，并描绘允许的进化路线，如序列变异模式所定义的，通过这些途径，病毒可以逃脱表位特异性抗体中和。3)确定病毒进化途径是否与病毒在体外的适合性和致病性以及体内病毒感染的临床结局相关。 相关性：随着禽流感病毒的传播继续造成广泛的经济和人类损失，预防人类感染禽流感已成为一项主要的公共卫生优先事项。这项研究的科学贡献将增加我们对病毒如何在免疫系统检测和消除后存活的理解，并为预防感染或临床疾病进展提供战略方法。

DESCRIPTION (provided by applicant): Highly pathogenic avian influenza virus H5N1 poses a debilitating pandemic threat. While prophylactic vaccines are being developed, ongoing viral evolution to evade immune responses remains problematic. Therefore, my long-term goals are to understand the antigenic evolution and molecular epidemiology of this virus in the face of selective immune pressure and to gain insights into the genesis and emergence of potentially pandemic strains. The central hypothesis is that viral escape mutants are constrained by specific interactions with neutralizing antibodies, and these mutants must evolve along defined, dominant, and reproducible evolutionary routes to escape from the immune pressure. The hypothesis is based, in part, on observations from epidemiological analysis of H5N1 virus from recent outbreaks in human populations. Some amino acids changes in hemagglutinin (HA) were involved in receptor binding and more frequently observed in human than in avian isolates, indicating that these viruses were antigenically distinct. This positive selection may be due to specific immune pressures as well as the process of viral adaptation to human hosts. I will test the hypothesis using human mAbs against the HA to define the pathways of H5N1 virus evolution under selective immune pressures. Additionally, I will correlate the specific routes of escape with clinical outcomes of influenza infection. In particular, I propose the following specific aims: 1) To characterize the epitopes of a panel of neutralizing and cross-neutralizing anti-H5 antibodies and their mechanisms of action. 2) To identify viral escape mutants induced by these antibodies and delineate the permitted evolutionary routes, as defined by patterns of sequence variations, by which the virus can escape epitope-specific antibody neutralization. 3) To determine if routes of virus evolution can be correlated with viral fitness and pathogenicity in vitro and clinical outcome of viral infection in vivo. RELEVANCE: Preventing human infections with bird flu has become a major public health priority as the virus continues to cause widespread economic and human losses as it spreads. The scientific contributions of this research will add to our understanding of how the virus survives detection and elimination by the immune system and provide strategic approaches to preventing infection or clinical disease progression.