Discovery and Targeting of HIV-1 Associated Antigens

HIV-1 相关抗原的发现和靶向

基本信息

批准号：
8493984
负责人：
William Hildebrand
金额：
$ 47.92万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-07 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8493984
关键词：
Alleles Antibodies Antigen Presentation Antigenic Variation Antigens Antiviral Agents Autoimmune Process Autoimmunity B-Lymphocytes Binding Bypass Cataloging Catalogs Cell Culture Techniques Cell Death Cell Line Cell surface Cells Complex Data Development Epitopes Flow Cytometry Frequencies Goals HIV HIV-1 HLA Antigens Human Immune Immune Targeting Immune response Immune system Infection Infectious Agent Mass Spectrum Analysis Memory Molecular Cloning Monoclonal Antibodies Nature Pattern Peptide Fragments Peptides Peripheral Blood Mononuclear Cell Proteins Proteome Proteomics Public Health Reporter Reverse Transcriptase Polymerase Chain Reaction Sampling Scanning Staining method Stains Surface T cell response T-Cell Antigen Receptor Specificity T-Cell Receptor T-Lymphocyte Testing Vaccination Viral Viral Physiology Viral Proteins Viremia Virus Virus Diseases cellular targeting coping efficacy testing fitness innovation novel response success transmission process vaccination strategy

项目摘要

DESCRIPTION (provided by applicant): While searching for HIV-1 peptides that distinguish the HLA class I of infected cells, we found that a number of host-derived peptides are unique to HIV-1 infected cells. In aim 1 we propose to discover HLA class I presented host peptides that distinguish HIV-1 infected cells. Using a unique immunoproteomics approach we will catalog targets that HIV-1 cannot antigenically vary. Having discovered host peptide/HLA complexes that distinguish infected cells, we will next pursue the immune targeting of these complexes. A concern in targeting host peptides presented by the HLA of HIV-1 infected cells is autoimmunity; T cell responses (including memory responses) might target host peptides on uninfected cells. In aim 2 we will derive monoclonal antibodies that mimic the T cell receptor's specificity for peptide/HLA complexes (TCR mimics or TCRm antibodies). The goal is to passively administer these TCRm antibodies for the targeting of HIV-1 infected cells. In aim 3 the anti-viral activity of these TCRm antibodies will be tested. In summary, we will apply a proven immunoproteomics approach to identify unrealized HLA presented host peptides that distinguish HIV-1 infected cells. Furthermore, we will target HIV-1 specific host peptides with a new class of antibodies: TCRm. These novel antibodies will be systematically tested for antiviral effects in cell lines, primary human PBMC and against primary HIV-1 isolates. The ultimate goal is to test whether passive administration of TCRm antibodies will impact HIV-1 replication while bypassing the autoimmune consequences of targeting host epitopes.) Public Health Statement: HIV has been able to elude or defeat immune responses that directly target the virus. We hypothesize that the indirect targeting of HIV infected cells can block transmission of the virus. The goal of this study is to first identify changes unique to the infected cell and to then indirectly attack HIV by targeting infected cells with a new class of antibodies. We intend to target factors that the virus requires rather than the virus itself.

描述（由申请人提供）：在寻找区分感染细胞I类HLA I类的HIV-1肽时，我们发现许多宿主衍生的肽是HIV-1感染细胞独有的。在AIM 1中，我们建议发现HLA I类提出了区分HIV-1感染细胞的宿主肽。使用独特的免疫蛋白质组学方法，我们将分类HIV-1不能抗原变化的靶标。在发现了区分受感染细胞的宿主肽/HLA复合物后，我们接下来将追求这些复合物的免疫靶向。靶向HIV-1感染细胞HLA提出的宿主肽的关注是自身免疫性。 T细胞反应（包括内存反应）可能靶向未感染的细胞上的宿主肽。在AIM 2中，我们将得出模仿T细胞受体对肽/HLA复合物（TCR模拟物或TCRM抗体）的单克隆抗体。目的是被动地施用这些TCRM抗体，以靶向HIV-1感染细胞。在AIM 3中，将测试这些TCRM抗体的抗病毒活性。总而言之，我们将采用一种经过验证的免疫蛋白质组学方法来识别未实现的HLA提出的宿主肽，这些宿主肽可以区分HIV-1感染的细胞。此外，我们将用新的抗体类别靶向HIV-1特异性宿主肽：TCRM。这些新型抗体将在细胞系，原代人PBMC和针对原代HIV-1分离株中系统测试。最终目标是测试被动施用TCRM抗体是否会影响HIV-1复制，同时绕过靶向宿主表位的自身免疫性后果。公共卫生声明：艾滋病毒已经能够躲避或击败直接针对该病毒的免疫反应。我们假设间接靶向HIV感染细胞可以阻止病毒的传播。这项研究的目的是首先识别受感染细胞独特的变化，然后通过用新的抗体靶向感染细胞来间接攻击HIV。我们打算针对病毒需要的因素，而不是病毒本身。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Abacavir induces loading of novel self-peptides into HLA-B*57: 01: an autoimmune model for HLA-associated drug hypersensitivity.

DOI：
10.1097/qad.0b013e328355fe8f
发表时间：
2012-07-17
期刊：
AIDS (London, England)
影响因子：
0
作者：
Norcross MA;Luo S;Lu L;Boyne MT;Gomarteli M;Rennels AD;Woodcock J;Margulies DH;McMurtrey C;Vernon S;Hildebrand WH;Buchli R
通讯作者：
Buchli R

Direct interrogation of viral peptides presented by the class I HLA of HIV-infected T cells.

直接询问 HIV 感染 T 细胞的 I 类 HLA 呈递的病毒肽。

DOI：
10.1128/jvi.01914-14
发表时间：
2014
期刊：
Journal of virology
影响因子：
5.4
作者：
Yaciuk,JaneC;Skaley,Matthew;Bardet,Wilfried;Schafer,Fredda;Mojsilovic,Danijela;Cate,Steven;Stewart,ChristopherJ;McMurtrey,Curtis;Jackson,KennethW;Buchli,Rico;Olvera,Alex;Cedeño,Samandhy;Plana,Montserrat;Mothe,Beatriz;Brander
通讯作者：
Brander

Expanding the targets available to therapeutic antibodies via novel disease-specific markers.