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（由申请人提供）：HIV研究迫切需要开发一种快速、廉价和准确的检测方法，可用于估计世界任何地方和任何样本的HIV发病率。在没有这种测试的情况下， 人口，传播模型，并监测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的发病率，以改善艾滋病毒的流行病学在资源匮乏的环境。这项研究的总体目标是使用一种尖端的免疫学检测方法，即全球HIV-1肽微阵列，来定义与HIV感染不同阶段相关的HIV特异性抗体的关键表位特征。我们的中心假设是，艾滋病毒感染的时间越长，多样性就越大 艾滋病毒特异性抗体。这项研究的基本原理是，一旦知道抗体表位特征与HIV感染的不同阶段相关，那么全球HIV-1肽微阵列就可以进一步发展为测量HIV发病率的工具。在强有力的初步数据的指导下，这一假设将通过追求两个特定目标进行检验：1）确定与HIV感染的三个不同阶段（近期、慢性病毒血症和ART抑制）相关的HIV特异性抗体的关键表位特征; 2）确定HIV血清学多样性如何与病毒血症受试者中随时间推移增加的HIV病毒多样性相关。在第一个目标下，我们将使用全球HIV-1肽微阵列对感染后已知时间的个体进行抗体表位作图。我们将用已建立的发病率测定法来补充肽微阵列，以测量抗体的大小和亲合力。当所提出的研究已经完成时，我们期望与最近的HIV感染相比，在非最近的HIV阶段中抗体表位特征的宽度将显著增加。在第二个目标下，我们将确定HIV表位特异性抗体应答的多样性（如通过肽微阵列测量的）和HIV病毒多样性（如通过单基因组扩增和桑格测序测量的）之间的关系，以提供对抗体进化的更好的病原学理解以及它如何与HIV发病率相关。当这些研究完成后，我们预计抗体结合的深度（在任何给定结合位点识别的序列变异数）将与随时间推移增加的HIV病毒多样性指标呈正相关。在我们看来，本申请中提出的研究是创新的，因为它引入了一种新的基于抗体的高通量检测方法，该方法有可能与病毒多样性检测方法一样对最近的HIV感染具有灵敏度和特异性。这项拟议的研究意义重大，因为它有望证明抗体表位特异性（通过抗体与HIV肽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，这些知识将为设计新的HIV发病率检测提供信息，这些检测将在HIV流行病学和诊断领域具有广泛的重要性。