Prospectively characterizing the functional and antigenic effects of mutations to viral entry proteins

前瞻性地表征病毒进入蛋白突变的功能和抗原效应

• 批准号: 10237969
• 负责人: Jesse D Bloom
• 金额: $ 9.59万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-24 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10237969
• 关键词: Address; Affect; Algorithms; Amino Acids; Animals; Antibodies; Antibody Therapy; Bar Codes; Binding; Biochemistry; Cell Culture Techniques; Cells; Complex; Ebola; Ebola virus; Epitopes; Evolution; Face; Genetic Recombination; Genomic approach; Growth; HIV; Health; Hearing; Human; Humoral Immunities; Immunity; Infection; Influenza; Lassa virus; Libraries; Link; Maps; Measles; Measurement; Measures; Methods; Middle East Respiratory Syndrome Coronavirus; Mutation; Nipah Virus; Nucleotides; Patients; Predisposition; Proteins; RNA Viruses; Research; Scourge; Smallpox; Techniques; Vaccination; Vaccines; Variant; Viral; Virion; Virus; Virus Diseases; Work; base; computerized tools; deep sequencing; mutant; mutation screening; neutralizing antibody; neutralizing monoclonal antibodies; news; prospective; receptor; receptor binding; tool; vaccine-induced immunity; virology

Viruses pose a constant threat to human health in substantial part because of the evolution of their entry proteins. This evolution can enable viruses to infect new species (including humans), and to evade antibody-based immunity. We will integrate approaches from genomics, computation, and virology to develop a general platform to prospectively characterize how mutations to a virus's entry protein affect its ability to infect cells and resist neutralization by antibodies. This platform can be used to study the entry proteins of an extremely wide range of viruses. We will use it to characterize the effects of all amino-acid mutations to the entry proteins from four important emerging viruses: Ebola virus, MERS coronavirus, Lassa virus, and Nipah virus. We will comprehensively identify mutations that affect the ability of these viruses to infect cells from relevant host species, and use the results to inform algorithms that assess a virus's host adaptation from sequence. We will also develop algorithms that leverage the platform to quantify how all mutations to a viral entry protein affect its susceptibility to antibody-based immunity. Overall, this work develops a powerful and general method to prospectively characterize the implications of viral mutations.

病毒在很大的部分对人类健康构成不断威胁 其进入蛋白的演变。这种进化可以使病毒感染新物种 （包括人类），并逃避基于抗体的免疫力。我们将整合 从基因组学，计算和病毒学的方法来开发一个通用平台到前瞻性 表征突变对病毒进入蛋白的影响如何影响其感染能力 细胞并通过抗体抵抗中和。该平台可用于研究 非常广泛的病毒的进入蛋白。我们将使用它来表征效果 从四个重要新兴病毒的所有氨基酸突变中的所有氨基酸突变中： 埃博拉病毒，MERS冠状病毒，Lassa病毒和Nipah病毒。我们将全面识别 影响这些病毒感染相关宿主物种细胞能力的突变，以及 使用结果通知算法，这些算法从序列中评估病毒的宿主适应性。我们 还将开发利用平台的算法来量化所有突变的方式 病毒进入蛋白会影响其对基于抗体免疫的敏感性。总体而言，这项工作 开发了一种强大而通用的方法，可以预期表征病毒的含义 突变。