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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.

此申请是为了申请续签BLR&D研究职业科学家（RCS）奖。