Debbink Kari, Lindesmith Lisa C, Ferris Martin T, Swanstrom Jesica, Beltramello Martina, Corti Davide, Lanzavecchia Antonio, Baric Ralph S
Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina, USA.
Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA.
J Virol. 2014 Jul;88(13):7244-55. doi: 10.1128/JVI.00203-14. Epub 2014 Mar 19.
Genogroup II, genotype 4 (GII.4) noroviruses are known to rapidly evolve, with the emergence of a new primary strain every 2 to 4 years as herd immunity to the previously circulating strain is overcome. Because viral genetic diversity is higher in chronic than in acute infection, chronically infected immunocompromised people have been hypothesized to be a potential source for new epidemic GII.4 strains. However, while some capsid protein residues are under positive selection and undergo patterned changes in sequence variation over time, the relationships between genetic variation and antigenic variation remains unknown. Based on previously published GII.4 strains from a chronically infected individual, we synthetically reconstructed virus-like particles (VLPs) representing early and late isolates from a small-bowel transplant patient chronically infected with norovirus, as well as the parental GII.4-2006b strain. We demonstrate that intrahost GII.4 evolution results in the emergence of antigenically distinct strains over time, comparable to the variation noted between the chronologically predominant GII.4 strains GII.4-2006b and GII.4-2009. Our data suggest that in some individuals the evolution that occurs during a chronic norovirus infection overlaps with changing antigenic epitopes that are associated with successive outbreak strains and may select for isolates that are potentially able to escape herd immunity from earlier isolates.
Noroviruses are agents of gastrointestinal illness, infecting an estimated 21 million people per year in the United States alone. In healthy individuals, symptomatic infection typically resolves within 24 to 48 h. However, symptoms may persist for years in immunocompromised individuals, and development of successful treatments for these patients is a continuing challenge. This work is relevant to the design of successful norovirus therapeutics for chronically infected patients; provides support for previous assertions that chronically infected individuals may serve as reservoirs for new, antigenically unique emergent strains; and furthers our understanding of genogroup II, genotype 4 (GII.4) norovirus immune-driven molecular evolution.
已知基因组II型4基因型（GII.4）诺如病毒进化迅速，每2至4年就会出现一种新的主要毒株，因为对先前流行毒株的群体免疫被突破。由于慢性感染中的病毒基因多样性高于急性感染，因此推测慢性感染的免疫功能低下人群可能是新的流行GII.4毒株的潜在来源。然而，虽然一些衣壳蛋白残基处于正选择状态，并且随着时间的推移在序列变异中经历有规律的变化，但基因变异与抗原变异之间的关系仍然未知。基于先前发表的来自一名慢性感染个体的GII.4毒株，我们合成重建了病毒样颗粒（VLP），其代表了一名长期感染诺如病毒的小肠移植患者的早期和晚期分离株，以及亲本GII.4 - 2006b毒株。我们证明，宿主内GII.4的进化会随着时间的推移导致抗原性不同的毒株出现，这与按时间顺序占主导地位的GII.4毒株GII.4 - 2006b和GII.4 - 2009之间的变异相当。我们的数据表明，在一些个体中，慢性诺如病毒感染期间发生的进化与与连续爆发毒株相关的不断变化的抗原表位重叠，并且可能选择出有可能逃避早期分离株群体免疫的分离株。
诺如病毒是胃肠道疾病的病原体，仅在美国每年就感染约2100万人。在健康个体中，有症状的感染通常在24至48小时内消退。然而，在免疫功能低下的个体中，症状可能会持续数年，为这些患者开发成功的治疗方法仍然是一项持续的挑战。这项工作与为慢性感染患者设计成功的诺如病毒治疗方法相关；为先前关于慢性感染个体可能作为新的、抗原性独特的新兴毒株储存库的断言提供了支持；并进一步加深了我们对基因组II型4基因型（GII.4）诺如病毒免疫驱动分子进化的理解。
