BLR&D Research Career Scientist Award

BLR

• 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
• 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

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.

本申请是为了申请延续BLR&D研究职业科学家（RCS）奖博士。 卡塔里纳海江。Hioe博士是James J. Peters VA Medical的研究健康专家（GS 13 Step 8） 中心（JJP VAMC），纽约州布朗克斯，和伊坎医学院的终身医学教授， 西奈她于1998年通过Merit Review Entry Program加入VA，并建立了她的研究实验室 最初在VA纽约港医疗保健系统-曼哈顿，2015年搬到JJP VAMC。她 收到了RCS奖励（10/1/12-9/30/17）和一年的成本延长至9/30/18，部分原因是回收 超级风暴桑迪（10/29/12）。尽管风暴的挫折，她的实验室继续出类拔萃，因为 在本申请中突出强调的每一项关键措施中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VA研究计划，研究艾滋病毒免疫学， 发病机制该计划还得到了一个强大的非退伍军人管理局研究计划的支持。Hioe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性 其可被宿主反应靶向以降低病毒传播性和感染性。尤其是，海江博士 研究集中在利用抗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抗体不属于本发明的范围。 广泛和有效的中和类别，而是靶向免疫原性保守位点，并且可以 由绝大多数个体产生。具体地，这些抗体靶向可变环1、2和3 (V1V2和V3），其形成HIV Env尖峰的顶点。尽管这些环具有可变的氨基酸， 它们保持被交叉反应性抗体识别的保守结构，所述抗体能够结合 来自多种亚型的不同分离株。重要的是，V1 V2抗体已被鉴定为免疫抑制剂。 泰国RV 144 HIV疫苗试验中HIV感染风险降低的相关性，这是唯一一项 显示出疫苗诱导的保护作用（尽管是短暂的，并且具有31.2%的适度功效）。抗V3抗体 在RV 144疫苗接种者的一个子集中，环也与较低的HIV感染率相关。 作为他们研究抗V1 V2和V3抗体如何赋予这种保护的结果，Hioe实验室 证明了以下主要发现：1）尽管V1 V2和V3抗体在体内没有显示出活性或活性较差， 标准的中和测定，它们的中和活性可以通过延长允许的时间来增强。 病毒-抗体相互作用;这表明HIV Env的高度动态性质，其影响V1 V2和V3 抗体的可及性。2)V1 V2和V3暴露也受包裹病毒Env的N-聚糖调节; 聚糖组成部分地由Env信号序列决定。因此，病毒对V1 V2和V3的易感性 抗体通过信号序列的变化来调节。3)V1 V2和V3抗体阻断HIV Env 共刺激活性，其增强CD 4 T细胞活化并使细胞对感染更敏感。 这种共刺激活性依赖于T细胞受体接合和抗原呈递细胞（APC）， 不需要感染性病毒，并且可以由具有可接近的V1 V2和V3的单体Env触发， 从而允许针对这些区域的抗体的有效阻断。4)最后，V1 V2和V3的被动转移 抗体导致在人源化小鼠模型中控制HIV感染，与在恒河猴中观察到的相似 用嵌合SHIV病毒攻击的猕猴。Hioe博士发表了32篇同行评审的研究文章， 在过去的10年里，报告这些和其他相关的研究。她指导了30多名学员， 参加了弗吉尼亚州内外的许多委员会。她还获得了一些 在2017年和2018年，她获得了NIH R21奖，以研究信号序列在调节 HIV Env表达和糖基化，NIH R 01资助评估非中和性抗病毒机制 抗体，以及VA Merit Review奖，以评估HIV与抗体和APC的相互作用。