Measurement of Antibody Epitope Signatures by Peptide Microarrays to Determine Recency of HIV Infection

通过肽微阵列测量抗体表位特征来确定 HIV 感染的新近程度

• 批准号: 9065192
• 负责人: Timothy Jensen Henrich
• 金额: $ 22.51万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-24 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9065192
• 关键词: AIDS prevention; Algorithms; Allergic Disease; Antibodies; Antibody Diversity; Antibody Response; Avidity; Award; Binding; Binding Sites; Biological Assay; Biological Markers; CD4 Positive T Lymphocytes; Cell Count; Chronic; Communicable Diseases; Complement; Complex; Cross-Sectional Studies; Data; Development; Diagnostic; Dideoxy Chain Termination DNA Sequencing; Epidemic; Epidemiology; Epitope Mapping; Epitopes; Evaluation; Evolution; Foundations; Genome; Goals; HIV; HIV Infections; HIV-1; Immune System Diseases; Immunology; Immunology procedure; Incidence; Individual; Infection; Knowledge; Laboratories; Lead; Longitudinal Studies; Measurement; Measures; Methods; Mission; Modeling; Monitor; Outcome; Peptide Library; Peptides; Performance; Persons; Plasma; Population; Prevention program; Public Health; Qualifying; RNA; Research; Research Project Grants; Resources; Sampling; Serological; Serum; Specificity; Specimen; Staging; Testing; Time; Variant; Viral; Viremia; Work; base; design; expectation; high risk; improved; innovation; novel; prevent; public health intervention; public health relevance; research study; specific biomarkers; tool; transmission process; vaccine trial; virology

 DESCRIPTION (provided by applicant): There is a critical need in HIV research to develop a rapid, inexpensive, and accurate assay that can be used to estimate HIV incidence anywhere in the world and on any sample. In the absence of such a test, it is challenging to identify high risk populations, model transmission, and monitor the outcome of public health interventions. Our long term goal is to develop new methods to measure HIV incidence to improve HIV epidemiology in resource-poor settings. The overall objective of the proposed research is to use a cutting-edge immunologic assay, the global HIV-1 peptide microarray, to define the key epitope signatures of HIV-specific antibodies associated with different stages of HIV infection. Our central hypothesis is that the greater the duration of HIV infection, the greater the diversity of HIV-specific antibodies. The rationale for the proposed research is that, once it is known that antibody epitope signatures are associated with different stages of HIV infection, then the global HIV-1 peptide microarray can be further developed as a tool to measure HIV incidence. Guided by strong preliminary data, this hypothesis will be tested by pursuing two specific aims: 1) to identify the key epitope signatures of HIV-specific antibodies that are associated with three different stages of HIV infection (recent, chronic viremia, and ART suppression); and 2) to determine how HIV serologic diversity is associated with increasing HIV viral diversity in viremic subjects over time. Under the first aim, we will perform antibody epitope mapping with a global HIV-1 peptide microarray on individuals with known time since infection. We will complement the peptide microarray with established incidence assays to measure antibody magnitude and avidity. When the proposed studies have been completed, it is our expectation that the breadth of antibody epitope signatures will be significantly increased in non-recent HIV stages compared to in recent HIV infection. Under the second aim, we will determine the relationship between diversity of HIV epitope- specific antibody responses (as measured by peptide microarray) and HIV viral diversity (as measured by single genome amplification and Sanger sequencing) to provide a better pathogenic understanding of antibody evolution and how it relates to HIV incidence. When these studies have been completed, it is our expectation that the depth of antibody binding (# sequence variants recognized at any given binding site) will be positively associated with increasing HIV viral diversity measures over time. The research proposed in this application is innovative, in our opinion, because it introduces a novel high-throughput antibody-based assay that has the potential to be as sensitive and specific for recent HIV infection as a viral diversity assay. The proposed research is significant, because it is expected to be the demonstration that antibody epitope specificity - as measured by the diversity of antibody binding to HIV peptides - can serve as a biomarker of different stages of HIV infection. Ultimately, such knowledge will inform the design of novel HIV incidence assays that will have broad importance in the fields of HIV epidemiology and diagnostics.

 描述（由适用提供）：艾滋病毒研究有一个迫切需要开发快速，廉价且准确的测定法，可用于估算世界上任何地方和任何样本的艾滋病毒发病率。在没有这样的测试的情况下，挑战要确定高风险 种群，模型传播和监视公共卫生干预措施的结果。我们的长期目标是开发新的方法来衡量艾滋病毒事件，以改善资源贫乏的环境中的艾滋病毒流行病学。拟议研究的总体目的是使用尖端的免疫学测定法，全球HIV-1肽微阵列来定义与HIV不同阶段相关的HIV特异性抗体的关键表位特征。我们的中心假设是，艾滋病毒感染的持续时间越大，多样性越多 HIV特异性抗体。拟议的研究的理由是，一旦知道抗体表位特征与HIV感染的不同阶段有关，则可以进一步开发全球HIV-1肽微阵列作为测量HIV入射的工具。在强有力的初步数据的指导下，将通过追求两个具体目的来检验该假设：1）确定与HIV感染的三个不同阶段有关的HIV特异性抗体的关键表位特征（最近，慢性病毒血症和艺术抑制）； 2）确定HIV血清学多样性如何与随着时间的流逝在病毒受试者中增加HIV病毒多样性有关。在第一个目标下，我们将对自感染以来已知时间的个体进行全局HIV-1肽微阵列进行抗体表位映射。我们将使用已建立的发病率测定剂来测量抗体幅度和亲和力的肽微阵列。当提出的研究完成后，我们期望与最近的HIV感染相比，非致命HIV阶段的抗体表位特征的广度将显着增加。在第二个目标下，我们将确定HIV表位特异性抗体反应的多样性（通过胡椒微阵列测量）和HIV病毒多样性（通过单个基因组扩增和Sanger测序衡量），以提供对抗体演化的更好的致病理解，并与HIV与HIV发病有关。当这些研究完成后，我们期望抗体结合的深度（在任何给定结合位点识别的＃序列变体）将与随着时间的推移增加HIV病毒多样性度量的增加呈正相关。在我们看来，在本应用程序中提出的研究具有创新性，因为它引入了一种新型的高通量抗体测定法，该测定可能对最近的HIV感染具有像病毒多样性测定的敏感和特异性。拟议的研究很重要，因为预计将是抗体表位特异性的证明 - 通过与HIV Pepperides的抗体结合的多样性来衡量 - 可以作为HIV感染不同阶段的生物标志物。最终，这些知识将为新型HIV事件评估的设计提供信息，这些评估将在HIV流行病学和诊断领域具有广泛的重视。