Determinants of Pathogenic Hantavirus Attachment

致病性汉坦病毒附着的决定因素

• 批准号: 7860323
• 负责人: Erich R Mackow
• 金额: $ 19.61万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-05 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7860323
• 关键词: Antibodies; Antibody Formation; Antiviral Agents; Binding; Binding Sites; Biochemical; Blocking Antibodies; Cleaved cell; Development; Disease; Endothelial Cells; Escape Mutant; Figs - dietary; Glycoproteins; Golgi Apparatus; Hantavirus; Hantavirus Infections; Hantavirus Pulmonary Syndrome; Hemorrhagic Fever with Renal Syndrome; Integrins; Mediating; Membrane Glycoproteins; Membrane Proteins; Peptides; Polyproteins; Protein Binding; Protein Structure Initiative; Proteins; Proteomics; Research; Retroviridae; Role; Surface; Tertiary Protein Structure; Testing; Therapeutic; Vascular Permeabilities; Viral; Viral Proteins; Virus; base; cell motility; crosslink; inhibitor/antagonist; neutralizing antibody; positional cloning; prevent; public health relevance; receptor; receptor binding; research study; therapeutic vaccine; trafficking

DESCRIPTION (provided by applicant): Hantaviruses infect endothelial cells (ECs) and cause 2 vascular permeability-based diseases: Hemorrhagic Fever with Renal Syndrome (HFRS) and Hantavirus Pulmonary Syndrome (HPS). Pathogenic hantaviruses bind to a 53 residue PSI domain present at the apex of bent, inactive, 1v23 integrins and dysregulate 1v23 integrin function (33, 73). The absence of 1v23 function is a known cause of vascular permeability and hemorrhagic disease, and only pathogenic hantaviruses bind 1v23. Hantavirus binding to 23 is RGD independent, however hantavirus attachment proteins and domains required for binding have not been discovered. We have identified 2 differences between surface proteins of pathogenic and non-pathogenic hantaviruses which correlate with 1v23 integrin usage. Here we will investigate the domains and residues of hantavirus surface glycoproteins required for pathogenic hantavirus binding to the 23 integrin PSI domain. Hantavirus surface proteins are synthesized as a polyprotein that is co-translationally cleaved into Gn and Gc fragments and trafficked to the cis-Golgi where hantavirus budding occurs. To date all pathogenic hantaviruses tested use 1v23 integrins for viral entry while non-pathogenic hantaviruses use discrete 1521 integrins. These findings suggest that unique changes in hantavirus Gn or Gc surface proteins are likely to differentiate viral attachment of pathogenic and non-pathogenic hantaviruses. We identified 2 Gc residue changes that are unique to non-pathogenic hantaviruses and not present in highly divergent pathogenic hantaviruses. Our studies of pathogenic hantavirus binding to 23 integrin PSI domains provide a basis for defining hantavirus proteins, domains and residues that mediate attachment. Proposed studies are likely to identify virus specific targets for the development of hantavirus therapeutics and vaccines and antibodies to viral attachment domains are likely to have direct therapeutic application. Objective: In this proposal we will define the domains and residues of pathogenic hantaviruses required for binding to 23 intergrin PSI domains and determine whether these domains elicit neutralizing antibody responses. Specific Aims: 1) Analyze PSI Domain Binding to Pathogenic Hantavirus Surface Proteins 2) GnGc Pseudotyped Virus Will be used to Define Requirements for 1v23 Binding 3) Antibodies to GnGc Peptides Required for PSI Binding will be evaluated for their ability to Inhibit Hantavirus Infection and PSI Domain Binding PUBLIC HEALTH RELEVANCE: Pathogenic hantaviruses bind to a small protein domain on 23 receptors called the PSI domain and targeting the viral protein that is responsible for binding to the 23 receptor is a viable means of inhibiting hantavirus infectivity and may be an antiviral therapeutic approach for regulating pathogenic hantavirus disease. Here we propose to define the viral protein components that are responsible for attaching the virus to the 23 PSI domain. Small pieces of hantavirus surface proteins will be analyzed for their ability to bind 1v23 PSI domains, block hantavirus infection, elicit antibodies that bind hantaviruses and prevent hantavirus interactions with cellular 1v23 receptors.

描述（由申请人提供）：汉坦病毒感染内皮细胞（ECS）并引起2种基于血管通透性的疾病：肾脏综合征（HFRS）和汉塔病毒肺综合症（HPS）的出血热。致病性汉坦病毒与存在于弯曲，无活性，1V23整联蛋白和失调1V23整联蛋白功能的53个残基PSI结构域结合（33，73）。 1V23功能的缺乏是血管通透性和出血性疾病的已知原因，并且只有致病性汉塔病毒结合1V23。汉坦病毒与23的结合是RGD独立的，但是尚未发现汉坦病毒的附着蛋白和结合所需的结构域。我们已经确定了与1V23整联蛋白使用相关的致病性汉坦病毒和非致病性汉坦病毒的表面蛋白之间的2个差异。在这里，我们将研究致病性汉塔病毒所需的汉塔病毒表面糖蛋白与23个整合素PSI结构域结合所需的结构域和残基。汉塔病毒表面蛋白合成为多蛋白，在跨裂片中裂解成GN和GC片段，并被贩运到hantavirus萌芽的顺式高尔基体中。迄今为止，测试的所有致病性汉坦病毒均使用1V23整联蛋白进行病毒输入，而非致病性汉坦病毒则使用离散的1521整联蛋白。这些发现表明，汉塔病毒GN或GC表面蛋白的独特变化可能会区分致病性和非致病性汉塔病毒的病毒附着。我们确定了2个GC残基的变化，这些变化是非致病性汉坦病毒所独有的，并且在高度不同的致病性汉坦病毒中不存在。我们对与23个整联蛋白PSI结构域结合的致病性汉塔病毒的研究为定义介导附着的汉塔病毒蛋白，结构域和残基提供了基础。拟议的研究很可能鉴定出病毒特定靶标，以开发汉坦病毒治疗剂，疫苗和对病毒附着域的抗体可能具有直接的治疗应用。目的：在此提案中，我们将定义与23个Intergrin PSI域结合所需的致病性汉坦病毒的域和残基，并确定这些结构域是否引起中和中和抗体反应。具体目的：1）分析PSI结构域与致病性汉塔病毒表面蛋白的结合2）GNGC伪型病毒将用于定义1V23结合的需求3）对PSI肽的抗体抗体所需的PSI肽所需的抗体，以评估其与hantavirus to antavirus Intication Atimant Intication Antavir intimant Intication Antaviragentions Intication Atimant Intication Antavir to nimain Intication a Intical Atimant aintive aintion Intication Antipagention： 23受体上的蛋白质结构域称为PSI结构域并靶向负责与23受体结合的病毒蛋白是抑制汉塔病毒感染性的可行手段，并且可能是调节致病性汉塔病毒疾病的抗病毒治疗方法。在这里，我们建议定义负责将病毒连接到23个PSI结构域的病毒蛋白成分。将分析小块汉坦病毒表面蛋白结合1V23 PSI结构域，阻断汉坦病毒感染，引起结合汉坦病毒并防止汉塔病毒与细胞1V23受体相互作用的抗体。