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.

本申请旨在申请续签BLR&D研究职业科学家(RCS)奖。 卡塔琳娜·霍伊。Hioe博士是詹姆斯·J·彼得斯退伍军人医疗中心的研究健康专家(GS13步骤8) 纽约布朗克斯市JJP VAMC中心(JJP VAMC)，芒特伊坎医学院终身医学教授 西奈半岛。1998年，她通过功绩审查入职计划加入退伍军人管理局，并建立了自己的研究实验室 最初在退伍军人事务部纽约港医疗系统-曼哈顿，2015年搬到JJP VAMC。她 获得RCS奖(10/1/12-9/30/17)，并将成本延长一年至9/30/18，部分原因是回收 来自超级风暴桑迪(2012年10月29日)。尽管遭受了那场风暴的挫折，但她的实验室继续表现出色，因为 在本申请中强调的每一项关键措施方面取得的一系列成就证明了这一点。 在过去的20年里，Hioe博士建立了一个退伍军人管理局研究项目，以研究艾滋病毒免疫学和 发病机制。这项计划还得到了一个强有力的非退伍军人研究计划的支持。Hloe实验室是 HIV包膜糖蛋白(Env)的免疫原性和免疫致病性研究 这可能是宿主反应的目标，以降低病毒的传播性和传染性。特别是，Hioe博士的 研究的重点是利用抗艾滋病毒环境抗体的抗病毒潜力，而不是 常规测量的病毒中和活性。感兴趣的抗环境病毒抗体不属于 广泛而有效的中和类别，但相反，目标是免疫原性保守的部位，并可以 由绝大多数个人产生。具体地说，这些抗体针对可变环1、2和3 (V1V2和V3)，这形成了HIV Env尖峰。尽管这些环有可变的氨基酸， 它们保持保守的结构，能够被能够结合HIV Env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抗体已被确认为一种免疫 在泰国RV144艾滋病毒疫苗试验中，艾滋病毒感染风险降低的相关性，这是唯一的III期临床试验 表现出疫苗诱导的保护作用(尽管时间很短，效力不大，仅为31.2%)。V3抗体 LOOP还与RV144疫苗接受者子集中较低的艾滋病毒获得率相关。 由于他们对抗V1V2和-V3抗体如何提供这种保护进行了研究，HIOE实验室 主要发现如下：1)虽然V1V2和V3抗体没有或表现出较低的活性 标准的中和分析表明，延长允许的时间可以增强它们的中和活性 病毒-抗体相互作用；这表明艾滋病毒环境病毒具有高度动态的性质，它影响V1V2和V3 抗体的可及性。2)V1V2和V3的暴露也受包裹病毒环境的N-糖链的调节； 糖链的组成部分由Env信号序列决定。因此，病毒对V1V2和V3的易感性 抗体受信号序列变化的调节。3)V1V2和V3抗体阻断HIV环境 共刺激活性，增强CD4T细胞的激活，使细胞更容易感染。 这种共刺激活性依赖于T细胞受体的参与和抗原提呈细胞(APC)， 不需要传染性病毒，可由V1V2和V3可及的单体环境蛋白触发， 允许抗体对这些区域进行有效的阻断。4)V1V2和V3的被动迁移 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 猕猴受到嵌合希夫病毒的挑战。Hioe博士发表了32篇同行评议的研究文章 在过去的10年里，报告了这些和其他相关的研究。她已经指导了30名实习生和 参加了退伍军人事务部内外的众多委员会。她还获得了多项荣誉 资助：2017年和2018年，她获得了美国国立卫生研究院R21奖，研究信号序列在调节中的作用 HIV env表达和糖基化，美国国立卫生研究院R01拨款评估非中和抗病毒机制 抗体，以及评估艾滋病毒与抗体和APC相互作用的VA功绩审查奖。