Dissecting the drivers of persistent SARS-CoV-2 infections

由β冠状病毒“严重急性呼吸道感染”引起的2019年冠状病毒病（COVID-19）大流行 冠状病毒2型综合征（SARS-CoV-2）是一种前所未有的公共卫生紧急情况。大多数患者 COVID-19在急性感染消退后清除病毒，但持续、持续、SARS-CoV-2 在免疫功能低下的个体中已经记录了复制。在这些慢性感染患者中， 在几周到几个月内恢复有复制能力的病毒与逐步获得 刺突内外的突变我们的初步数据表明，这种长时间的宿主内病毒进化 在新的、抗原性不同的SARS-CoV-2变体的出现中起作用。我们建议系统地 使用综合转化研究阐明SARS-CoV-2持续感染的决定因素 方法结合现实世界的临床元数据与生物信息学，基因组学和分子病毒学。我们将 利用现有的大型监测数据集，涵盖两年半的SARS-CoV-2传播， 约克市回到2020年春季大流行开始时，纽约大都会地区 成为大流行病的早期中心之一。具体目标1将剖析临床特征， 使用现有的纵向数据与SARS-CoV-2持续复制相关的治疗干预 电子病历。这些研究将通过分析B和T细胞群来补充 持续感染的病人。具体目标2将剖析代表宿主内 长期的演变，特别强调共循环病毒变异。第3章将 研究持续性SARS-CoV-2变异体的表型特性，重点是趋同进化 在尖峰区域之内和之外（对中和、融合、尖峰处理和 干扰素拮抗作用）。 总而言之，拟议的研究解决了关于生物驱动因素和病毒的关键知识差距 在持续的SARS-CoV-2感染期间，动力学促进了SARS-CoV-2病毒变异体的选择。这 知识将提供治疗和预防这种慢性感染所需的科学基础， 越来越多的耐中和但可传播的SARS-CoV-2变种的出现和传播。

The coronavirus disease 2019 (COVID-19) pandemic caused by the betacoronavirus “severe acute respiratory syndrome coronavirus 2” (SARS-CoV-2) represents an unprecedented public health emergency. Most patients with COVID-19 clear the virus upon resolution of the acute infection but ongoing, persistent, SARS-CoV-2 replication has been documented in immunocompromised individuals. In these chronically infected patients, recovery of replication-competent virus over several weeks to months is linked to stepwise acquisition of mutations within and outside of spike. Our preliminary data show that such prolonged intra-host viral evolution plays a role in the emergence of new, antigenically distinct, SARS-CoV-2 variants. We propose to systematically elucidate the determinants of persistent SARS-CoV-2 infections using an integrated translational research approach combining real-world clinical metadata with bioinformatics, genomics and molecular virology. We will leverage an existing large surveillance dataset covering two and a half years of SARS-CoV-2 spread in New York City going back to the beginning of the pandemic in the spring of 2020 when the NY metropolitan area emerged as one of the early epicenters of the pandemic. Specific Aim 1 will dissect the clinical features and therapeutic interventions associated with persistent SARS-CoV-2 replication using existing longitudinal data from electronic medical records. These studies will be complemented by the analysis of the B and T cell populations of persistently infected patients. Specific Aim 2 will dissect the viral genotypes representative of intra-host evolution of prolonged periods with a special emphasis on co-circulating viral variants. Specific Aim 3 will examine the phenotypic properties of persistent SARS-CoV-2 variants with an emphasis on convergent evolution within and outside of the spike region (susceptibility to neutralization, fusogenicity, spike processing and interferon antagonism). Altogether, the proposed studies address a critical knowledge gap regarding the biological drivers and viral dynamics fueling the selection of SARS-CoV-2 viral variants during persistent SARS-CoV-2 infection. This knowledge will provide the scientific basis needed to treat and prevent such chronic infections thereby limiting the emergence and spread of increasingly neutralization-resistant yet transmissible SARS-CoV-2 variants.