STRUCTURE AND FUNCTION OF ALEUTIAN MINK DISEASE PARVOVIRUS (ADV) GENOME

阿留申水貂病细小病毒 (ADV) 基因组的结构和功能

• 批准号: 6431534
• 负责人: Marshall Elliott Bloom
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6431534
• 关键词: Baculoviridae; Carnivora; Parvoviridae; X ray crystallography; capsid; computer assisted sequence analysis; cryoscopy; genome; host organism interaction; laboratory rabbit; microorganism culture; microorganism immunology; nucleic acid sequence; protein structure function; recombinant virus; virion; virulence; virus antigen; virus genetics

Persistent infection of mink with Aleutian mink disease parvovirus (ADV) leads to progressive immune disorder characterized by high levels of antiviral antibodies, hypergammaglobulinemia, plasmacytosis, and immune complex disease. Virus is not neutralized in vivo and ADV exists in infectious immune complexes. Isolates of ADV differ markedly in their ability to induce AD. A major goal of this project is to correlate specific DNA sequences of the ADV genome to functional correlates, such as pathogenicity determinants and strain variation. A second goal is to characterize an ADV-binding protein (ABP)on the surface of susceptible cells that specifically binds ADV capsids and is th putative cellular receptor. A third major goal is to study the actual structure of the ADV virion. Understanding of the structure at high resolution will enable us to (a) map epitopes and pathogenicity determinants to discreet coordinates on the viral particle, (b) relate structural features to the unique biology of ADV in vivo. In the past year, work on this project led to a number of findings. N-terminal sequencing of ABP revealed an amino acid motif common to beta-tubulin like proteins. By studying additional chimeric and site-directed mutant ADV, we found that the expression of pathogenicity requires cooperative interactions of non-adjacent capsid protein amino acids. A neutralizing epitope has been mapped to the shoulder of the protrusions vicinal to the 3-fold axes of symmetry, and this epitope overlaps with a sequence mediating antibody-dependent enhancement (ADE) of infection. An additional and distinct sequence mediating ADE maps to amino acid residues contributing to the protrusions proper.

阿留申貂皮病细节病毒（ADV）对貂皮的持续感染导致进行性免疫疾病，其特征是高水平的抗病毒药抗体，高γ-球胶质素血症，浆细胞增多症和免疫复杂疾病。病毒不会在体内中和，并且在传染性免疫复合物中存在ADV。 ADV的分离株在诱导AD的能力方面显着不同。该项目的主要目标是将ADV基因组的特定DNA序列与功能相关性相关联，例如致病性决定因素和应变变异。第二个目标是表征易感细胞表面上的ADV结合蛋白（ABP），该蛋白质特异性地结合了ADV CAPSID，并且是推定的细胞受体。第三个主要目标是研究Adv Virion的实际结构。对高分辨率下的结构的理解将使我们能够（a）映射表位和致病性决定因素，以划分病毒粒子上的坐标，（b）将结构特征与adv in Vivo的独特生物学相关联。在过去的一年中，该项目的工作导致了许多发现。 ABP的N末端测序表明，β-微管蛋白像蛋白一样常见的氨基酸基序。通过研究其他嵌合和定位的突变体ADV，我们发现致病性的表达需要非粘质的衣壳蛋白氨基酸的合作相互作用。中和表位已被映射到横长的突起的肩膀上，与对称的3倍轴，该表位与介导抗体依赖性增强（ADE）的序列重叠。另外且独特的序列将ADE图介导了氨基酸残基，这些氨基酸残基有助于促进突起。