BLR&D Research Career Scientist Award

BLR

• 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
• 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

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。 卡塔琳娜·希惠. 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 西奈半岛。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。她 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 (10/29/2012)。尽管遭受了那场风暴的挫折，她的实验室仍然表现出色， 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 发病。该计划还得到了强大的非 VA 研究计划的支持。日江实验室是 研究 HIV 包膜 (Env)（一种糖蛋白）的免疫原性和免疫致病特性 这可能是宿主反应的目标，以减少病毒的传播性和传染性。特别是，Hioe 博士的 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。感兴趣的抗 Env 抗体不属于 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 由绝大多数个人产生。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。 来自多个亚型的不同分离株。重要的是，V1V2 抗体已被确定为一种免疫 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 显示出疫苗诱导的保护作用（尽管持续时间较短且功效有限，仅为 31.2%）。 V3 抗体 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 证明了以下主要发现：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 包膜具有高度动态的性质，它会影响 V1V2 和 V3 抗体的可及性。 2）V1V2和V3暴露也受到覆盖病毒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敏感 抗体受信号序列变化的调节。 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）最后被动转移V1V2和V3 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 猕猴受到嵌合 SHIV 病毒的攻击。 Hioe 博士发表了 32 篇同行评审的研究文章 过去 10 年报告这些研究和其他相关研究。她指导过超过 30 名学员 参加了 VA 内外的许多委员会。她还荣获多项 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。