Studies on the Epidemiology of H5N1 Influenza Evolution

描述（由申请方提供）：高致病性禽流感病毒H5N1构成了一种使人衰弱的大流行威胁。虽然正在开发预防性疫苗，但正在进行的病毒进化以逃避免疫应答仍然存在问题。因此，我的长期目标是了解这种病毒在面对选择性免疫压力时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。核心假设是，病毒逃逸突变体受到与中和抗体的特异性相互作用的限制，这些突变体必须沿着沿着确定的、显性的和可重复的进化路线进化，以逃避免疫压力。这一假设部分是基于对最近在人群中爆发的H5N1病毒进行流行病学分析的观察结果。血凝素（HA）中的一些氨基酸变化参与受体结合，并且在人中比在禽分离株中更频繁地观察到，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。我将使用抗HA的人单克隆抗体来确定H5N1病毒在选择性免疫压力下的进化途径，以验证这一假设。此外，我将把特定的逃逸途径与流感感染的临床结局联系起来。特别是，我提出了以下具体目标：1）表征一组中和和交叉中和抗H5抗体的表位及其作用机制。2)鉴定这些抗体诱导的病毒逃逸突变体，并描述允许的进化路线，如序列变异模式所定义，病毒可通过该路线逃避表位特异性抗体中和。3)确定病毒进化途径是否与体外病毒适应性和致病性以及体内病毒感染的临床结局相关。 相关性：预防人类感染禽流感已成为一个主要的公共卫生优先事项，因为该病毒在传播过程中继续造成广泛的经济和人类损失。这项研究的科学贡献将增加我们对病毒如何在免疫系统的检测和消除中存活的理解，并提供预防感染或临床疾病进展的战略方法。

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.