BLR&D Research Career Scientist Award

BLR

基本信息

批准号：
10265409
负责人：
Catarina E Hioe
金额：
--
依托单位：
JAMES J PETERS VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10265409
关键词：
AIDS prevention Admission activity Affect Amino Acids Anti-Retroviral Agents Antibodies Antigen-Presenting Cells Antigens Antiviral Agents Applications Grants Appointment Award Binding Biological Assay Blocking Antibodies Book Chapters CD4 Positive T Lymphocytes Caring Categories Cells Cellular Assay Cleaved cell Clinical Immunology Coculture Techniques Collaborations Communicable Diseases Contracts Data Development Disease Endoplasmic Reticulum Epitopes Exploratory/Developmental Grant for Diagnostic Cancer Imaging Fluorescence Microscopy Foundations Funding Glycoproteins Goals Grant HIV HIV Infections HIV vaccine Health Healthcare Systems High School Student IACUC Image Immune Immune response Immunity Immunology Individual Infection Interleukin-2 Investigation Israel Knowledge Laboratories Laboratory Research Lectin Lipid Bilayers Macaca mulatta Mass Spectrum Analysis Measures Mediating Medical center Medicine Mentors Mentorship Molecular Virology Mutation National Institute of Allergy and Infectious Disease Nature New York Oligosaccharides Paper Pathogenesis Pathogenicity Peptide Signal Sequences Phase Phase III Clinical Trials Polysaccharides Post-Translational Protein Processing Postdoctoral Fellow Predisposition Process Property Provider Publications Publishing Recovery Reporting Research Research Peer Review Research Training Risk Role Science Scientist Site Specialist Stream Structure Study Section T-Cell Activation T-Cell Receptor T-Lymphocyte Therapeutic Time Training Trust United States National Institutes of Health V3 Loop Vaccination Vaccine Research Vaccines Veterans Viral Antigens Virus Virus Diseases Western Blotting Work Yang career cost cross reactivity design editorial env Gene Products falls frontier glycosylation graduate student humanized mouse immunogenic interest medical schools monocyte monomer mouse model neutralizing antibody novel pathogen prevent professor programs prophylactic response simian human immunodeficiency virus standard of care technique development tool undergraduate student vaccine trial vaccine-induced immunity viral transmission virus development virus envelope

项目摘要

This application is to request a renewal of the BLR&D Research Career Scientist (RCS) award for Dr. Catarina Hioe. Dr. Hioe is a Research Health Specialist (GS13 Step 8) at the James J. Peters VA Medical Center (JJP VAMC), Bronx, NY, and a tenured Professor of Medicine at the Icahn School of Medicine at Mount Sinai. She joined the VA via the Merit Review Entry Program in 1998 and established her research laboratory initially at the VA New York Harbor Healthcare System–Manhattan, moving in 2015 to the JJP VAMC. She received an RCS award (10/1/12-9/30/17) and a one-year Cost Extension through 9/30/18, in part for recovery from Superstorm Sandy (10/29/12). Despite the setback from that storm, her lab continues to excel, as evidenced by an array of accomplishments in each of the key measures that are highlighted in this application. Over the past 20 years, Dr. Hioe has built a VA research program to study HIV immunology and pathogenesis. This program is also supported by a robust non-VA research program. The Hioe lab is investigating the immunogenic and immunopathogenic properties of the HIV envelope (Env), a glycoprotein that may be targeted by host responses to reduce virus transmissibility and infectivity. In particular, Dr. Hioe's studies have focused on harnessing the antiviral potential of anti-HIV Env antibodies beyond their conventionally measured virus-neutralizing activity. The anti-Env antibodies of interest do not fall into the broadly and potently neutralizing category but, instead, target immunogenic conserved sites and can be generated by the vast majority of individuals. Specifically, these antibodies target the variable loops 1, 2, and 3 (V1V2 and V3), which form the apex of an HIV Env spike. Although these loops have variable amino acids, they maintain conserved structures that are recognized by cross-reactive antibodies able to bind HIV Env of diverse isolates from multiple subtypes. Importantly, V1V2 antibodies have been identified as an immune correlate of reduced risk of HIV acquisition in the Thai RV144 HIV vaccine trial, the only phase III clinical trial to show vaccine-induced protection (albeit short-lived and with a modest efficacy of 31.2%). Antibodies to the V3 loop also correlated with lower rates of HIV acquisition in a subset of RV144 vaccine recipients. As a result of their research into how anti-V1V2 and -V3 antibodies confer this protection, the Hioe lab has demonstrated the following major findings: 1) Although V1V2 and V3 antibodies display no or poor activity in standard neutralization assays, their neutralizing activity can be enhanced by prolonging the time allowed for virus-antibody interaction; this is indicative of the highly dynamic nature of HIV Env, which affects V1V2 and V3 accessibility to antibodies. 2) V1V2 and V3 exposure is also regulated by N-glycans that shroud the virus Env; glycan composition is dictated in part by Env signal sequence. Hence, virus susceptibility to V1V2 and V3 antibodies is modulated by signal sequence changes. 3) V1V2 and V3 antibodies block the HIV Env costimulatory activity that enhances CD4 T cell activation and renders the cells more susceptible to infection. This costimulatory activity is dependent on T-cell receptor engagement and antigen-presenting cells (APCs), does not require infectious virus, and can be triggered by monomeric Env with accessible V1V2 and V3, allowing effective blockade by antibodies against these regions. 4) Finally, passive transfer of V1V2 and V3 antibodies results in control of HIV infection in the humanized mouse model, similar to that seen in rhesus macaques challenged with a chimeric SHIV virus. Dr. Hioe has published 32 peer-reviewed research articles over the past 10 years to report these and other, related studies. She has mentored >30 trainees and participated in numerous committees within and outside the VA. She also has been awarded a number of grants: In 2017 and 2018, she received an NIH R21 award to study the role of signal sequence in regulating HIV Env expression and glycosylation, an NIH R01 grant to assess antiviral mechanisms of non-neutralizing antibodies, and a VA Merit Review award to evaluate HIV interaction with antibodies and APCs.

本申请旨在请求为 BLR&D 博士续签 BLR&D 研究职业科学家 (RCS) 奖。 Catarina Hioe 博士是 James J. Peters VA Medical 的研究健康专家（GS13 步骤 8）纽约布朗克斯中心 (JJP VAMC) 和芒特伊坎医学院终身教授她于 1998 年通过择优录取计划加入 VA，并建立了自己的研究实验室。最初在 VA 纽约港医疗系统 - 曼哈顿，于 2015 年搬到 JJP VAMC。获得 RCS 奖励（2012 年 10 月 1 日至 2017 年 9 月 30 日）以及截至 2018 年 9 月 30 日的一年费用延期，部分用于回收来自超级风暴桑迪（2012 年 10 月 29 日），尽管遭受了风暴的挫折，她的实验室仍然表现出色，因为本申请中强调的每项关键措施都取得了一系列成就，证明了这一点。在过去的 20 年里，Hioe 博士建立了一个 VA 研究项目来研究 HIV 免疫学和该计划还得到了 Hioe 实验室强大的非 VA 研究计划的支持。研究 HIV 包膜 (Env)（一种糖蛋白）的免疫原性和免疫致病特性可能是宿主反应的目标，以减少病毒的传播性和传染性。研究重点是利用抗 HIV Env 抗体的抗病毒潜力常规测量的病毒中和活性不属于感兴趣的抗-Env 抗体。广泛且有效的中和类别，但相反，目标是免疫原性保守位点，并且可以具体来说，这些抗体针对可变环 1、2 和 3 （V1V2 和 V3），形成 HIV 包膜尖峰的顶点尽管这些环具有可变的氨基酸，它们保持保守的结构，能够被能够结合 HIV 包膜的交叉反应抗体识别。重要的是，V1V2 抗体已被鉴定为一种免疫抗体。泰国 RV144 HIV 疫苗试验中艾滋病毒感染风险降低的相关性，该试验是唯一的 III 期临床试验显示疫苗诱导的保护（尽管短暂且针对 V3 的抗体效力有限，为 31.2%）。 Loop 还与 RV144 疫苗接种者中 HIV 感染率较低相关。 Hioe 实验室研究了抗 V1V2 和 -V3 抗体如何提供这种保护，结果以下主要发现：1）尽管 V1V2 和 V3 抗体在标准中和测定，可以通过延长允许的时间来增强其中和活性病毒-抗体相互作用；这表明 HIV 包膜具有高度动态性，会影响 V1V2 和 V3 2) V1V2 和 V3 暴露也受到病毒 Env 周围 N-聚糖的调节；聚糖组成部分由 Env 信号序列决定，因此，病毒对 V1V2 和 V3 的易感性。 3) V1V2 和 V3 抗体阻断 HIV 包膜共刺激活性增强 CD4 T 细胞活化并使细胞更容易受到感染。这种共刺激活性依赖于 T 细胞受体的参与和抗原呈递细胞 (APC)，不需要传染性病毒，并且可以由具有可访问的V1V2和V3的单体Env触发，允许针对这些区域的抗体有效阻断4)最后，V1V2和V3的被动转移。抗体在人源化小鼠模型中控制艾滋病毒感染，类似于在恒河猴中看到的结果 Hioe 博士发表了 32 篇经过同行评审的研究文章。在过去的 10 年里，她指导了超过 30 名学员和其他相关研究。她参加了 VA 内外的许多委员会，并获得了多项奖项。资助：2017年和2018年，她获得了NIH R21奖，以研究信号序列在调节中的作用 HIV Env 表达和糖基化，NIH R01 资助，用于评估非中和性的抗病毒机制抗体，以及 VA 优异评审奖，以评估 HIV 与抗体和 APC 的相互作用。