IMMUNOGENIC SUGAR MOIETIES OF HCMV

项目摘要-摘要 人巨细胞病毒(HCMV)感染在免疫低下人群中引起严重的发病率/死亡率 并导致先天感染后的高出生缺陷率。因此，巨细胞病毒疫苗的开发是一项 公共卫生优先事项。然而，hcmv是最复杂的人类病毒之一，其范围也是独一无二的。 在广泛的人类细胞中具有传染性。识别保守的分子靶标对于 阻断人巨细胞病毒的多种感染性。 最近，我们进行了一项调查，以探索不同系统起源的病毒，如 人巨细胞病毒、人类免疫缺陷病毒1型(HIV-1)和严重急性呼吸综合征冠状病毒(SARS- CoV)，表达适合广谱病毒中和的保守糖基决定簇。我们 假设病毒依赖宿主糖基化机制来合成多糖，从而可以表达 保守的病毒碳水化合物。这项研究导致了一些隐蔽的糖链标记的鉴定 被这些病毒过度表达。重要的是，这些碳水化合物携带有效的病毒中和表位和 是一种广谱病毒中和剂雪花莲凝集素(GNA)的特定靶标。 这些发现促使我们进一步研究HCMV显示的这些碳水化合物是否 在体内产生免疫原性，从而成为免疫干预的关键靶点，以对抗HCMV感染。 具体地说，我们将进行跨物种碳水化合物微阵列研究，以检查宿主是否对 系统识别并安装针对这些目标的中和抗体反应(目标1)。此外，我们将采取 一大批具有明确特异性的抗糖蛋白单抗和凝集素的优势 广谱病毒中和抗体针对的主要抗原决定簇(目标2)。 [综上所述，我们提出了两种互补的方法来识别潜在的免疫原性碳水化合物 这是开发新型抗人巨细胞病毒糖结合疫苗的关键步骤。这个 在HCMV疫苗方面拥有独特专业知识的主要合作者大大增强了这一提议的力度 发展、碳水化合物抗原的化学-酶合成，以及医院中的巨细胞病毒保健。自.以来 目标碳水化合物也被其他病毒病原体过度表达并暴露在表面，例如 HIV-1、SARS-CoV和埃博拉病毒，这项研究可能会提供关键信息，指导生产 抗多聚糖抗体的鸡尾酒，很容易用于对广泛的 病毒病原体。

PROJECT SUMMARY-ABSTRACT Human cytomegalovirus (HCMV) infection causes serious morbidity/mortality in immune-compromised patients and leads to high rates of birth defects after congenital infection. HCMV vaccine development is thus a public health priority. However, HCMV is one of the most intricate human viruses and unique in its broad-range infectivity in a wide range of human cells. Identifying conserved molecular targets is of critically importance for blocking the versatile infectivity of HCMV. Recently, we undertook an investigation to explore whether viruses of distinct phylogenetic origins, such as HCMV, human immunodeficiency virus 1 (HIV-1), and severe acute respiratory syndrome coronavirus (SARS- CoV), express conserved glyco-determinants that are suitable for broad-spectrum virus neutralization. We assumed that viruses depend on host glycosylation machinery for glycan synthesis and thereby may express the conserved viral carbohydrates. This study has led to identification of a number of cryptic glycan markers overexpressed by these viruses. Importantly, these carbohydrates carry potent virus-neutralizing epitopes and are specifically targeted by a broad-spectrum virus-neutralizing agent, Galanthus nivalis lectin (GNA). These findings prompt us to further investigate whether these carbohydrates, as displayed by HCMV, are immunogenic in vivo and thereby serve as key targets for immunological intervention against HCMV infection. Specifically, we will perform a cross-species carbohydrate microarray study to examine whether host immune systems recognize and mount neutralizing antibody responses to these targets (Aim 1). Moreover, we will take advantage of a large panel of anti-glycan monoclonal antibodies and lectins of defined specificities to pinpoint the dominant antigenic determinants that are targeted by broad-spectrum virus-neutralizing antibodies (Aim 2). [In summary, we propose two complementary approaches to identify potential immunogenic carbohydrate moieties of HCMV, which is a critical step for developing novel glyco-conjugate vaccines against HCMV.] The strength of this proposal is substantially enhanced by key collaborators with unique expertise in HCMV vaccine development, chemo-enzymatic synthesis of carbohydrate antigens, and HCMV healthcare in hospitals. Since the targeted carbohydrates are also overexpressed and surface-exposed by other viral pathogens, such as HIV-1, SARS-CoV, and the Ebola virus, this study may provide key information to guide the production of a cocktail of anti-glycan antibodies that are readily applicable for passive immunization against a broad range of viral pathogens.