BLR&D Research Career Scientist Award

BLR

基本信息

批准号：
9754929
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/9754929
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.

该申请是为了申请续签BLR＆D研究职业科学家（RCS）博士奖。 Catarina Hioe。 Hioe博士是James J. Peters VA Medical的研究健康专家（GS13步骤8）纽约州布朗克斯市的中心（JJP VAMC），以及芒特伊坎医学院的终身医学教授西奈。她通过1998年的优异审查条目计划加入VA，并建立了她的研究实验室最初在纽约港口医疗保健系统 - 曼哈顿，2015年搬到JJP VAMC。她获得了RCS奖（10/1/1/12-9/30/17），并在9/30/18获得了一年的成本延长，部分用于恢复来自Superstorm Sandy（10/29/12）。尽管这场风暴遭受了挫折，但她的实验室仍在继续表现在本应用程序中突出显示的每个关键措施中的一系列成就都证明了这一点。在过去的20年中，Hioe博士建立了VA研究计划，以研究HIV免疫学和发病。该计划也得到了强大的非VA研究计划的支持。 Hioe实验室是研究糖蛋白的HIV包膜（ENV）的免疫原性和免疫发育特性这可能是通过宿主反应来靶向的，以减少病毒传播和感染。特别是Hioe博士研究的重点是利用抗HIV ENV抗体的抗病毒潜力以外常规测量的病毒中和活性。感兴趣的抗ENV抗体不会属于广泛而潜在的中和类别，但是，靶向免疫原性组成部位，可以是由绝大多数个人产生。具体而言，这些抗体靶向变量环1、2和3 （V1V2和V3），构成了HIV Env Spike的顶点。尽管这些环具有可变的氨基酸，但他们维护组成的结构，这些结构通过能够结合HIV的交叉反应抗体识别来自多种亚型的各种分离株。重要的是，V1V2抗体已被确定为免疫在泰国RV144 HIV疫苗试验中，HIV获取风险降低的相关性是唯一的III期临床试验显示疫苗诱导的保护（尽管短暂且易于31.2％）。 V3的抗体环路还与RV144疫苗接种者子集中的HIV获取率较低有关。由于他们研究了抗V1V2和-V3抗体如何进行此保护的研究，Hioe Lab具有证明了以下主要发现：1）虽然V1V2和V3抗体在没有表现出或不良活性标准谈判测定法，可以通过延长允许的时间来增强其中和活动病毒抗体相互作用；这表明影响V1V2和V3的HIV Env的高度动态性质 2）V1V2和V3暴露还受到病毒env的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的敏感性抗体由信号序列变化调节。 3）V1V2和V3抗体阻止HIV Env 共刺激活性增强了CD4 T细胞活化并使细胞更容易感染。这种共刺激活性取决于T细胞受体的参与和抗原呈递细胞（APC），不需要传染病，可以由可访问的V1V2和V3触发。允许对这些区域的抗体有效阻断。 4）最后，V1V2和V3的被动转移抗体导致人性化小鼠模型中HIV感染的控制，类似于恒河猴猕猴面对嵌合SHIV病毒挑战。 Hioe博士发表了32份同行评审的研究文章在过去的10年中，报告这些和其他相关研究。她指导了30名学员，参加VA内外的许多委员会。她也被授予了许多赠款：在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，一种NIH R01赠款，用于评估非中和化的抗病毒机制抗体，以及评估与抗体和APC的艾滋病毒相互作用的VA功绩审查奖。