Contributions of anti-V2 antibodies in protection against HIV

抗 V2 抗体在预防 HIV 方面的贡献

基本信息

批准号：
8515934
负责人：
Catarina E Hioe
金额：
$ 52.46万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8515934
关键词：
AIDS/HIV problem ALVAC Accounting Active Immunization Address Antibodies Antibody Formation Binding Bioinformatics Biological Assay Breathing CD4 Positive T Lymphocytes Case-Control Studies Cells Collaborations Data Development Epitopes Exhibits Future Goals HIV HIV Envelope Protein gp120 HIV Genome HIV Infections HIV vaccine HIV-1 Homing Human Immune Immunoglobulin G In Vitro Integrins International Investigation Knowledge Length Measurement Measures Mediating Monoclonal Antibodies Mus Names Phase Proteins Reporting Route Series Site Structure Surrogate Markers T-Lymphocyte Temperature Testing Time Vaccination Vaccines Variant Viral Physiology Virus Virus Diseases West Nile virus adaptive immunity cross reactivity design human monoclonal antibodies in vitro Assay in vitro activity in vivo insertion/deletion mutation neutralizing antibody pandemic disease polyclonal antibody prevent prophylactic protective effect receptor research study response success transmission process

项目摘要

DESCRIPTION (provided by applicant): Immune effector mechanisms that confer protection against HIV acquisition remains poorly understood. Recent data from the Phase III RV144 trial of the prime/boost ALVAC+gp120 protein vaccine, which delivered an overall 31.2% reduction in virus acquisition, suggest potential protective effects of anti-gp120 antibody responses. Specifically, of the six primary immunological parameters evaluated in the RV144 case-control study, high IgG responses to the V2 loop of HIV envelope gp120 significantly correlate with protection from HIV infection. However, it is unclear if anti-V2 antibodies have direct anti-viral functions for blocking HIV infection. V2 and other variable loops of gp120 are thought to be undesirable targets for HIV vaccines, due to their highly variable sequences. While a closer scrutiny of V2 sequences has demonstrated a significant level of AA conservation including a conserved LDV/I motif, which is involved in binding ¿4¿7 integrin, the gut homing receptor expressed on key CD4 T cell targets for mucosal transmission, anti-V2 antibodies have little or no neutralizing activities against many HIV-1 primary isolates when measured under conventional assay conditions and with target cells expressing no ¿4¿7. We propose herein to utilize non-conventional in vitro and in vivo approaches to investigate the capacity of anti-V2 antibodies to block HIV transmission. We will first measure the ability of anti-V2 human monoclonal antibodies to block virus infection in vitro by varying incubation time, temperature, target CD4 T cells with or without active ¿4¿7, cell-free and cell-to-cell transmission. Secondly, we will test human anti-V2 monoclonal antibodies in vivo for the ability to reduce HIV acquisition in passive transfer and virus challenge in humanized mice. Finally, we will evaluate the ability of polyclonal anti-V2 antibodies raised by vaccination to mediate virus blocking in vitro and in vivo. Our results will define the potential contributions of anti-V2 antibody response in preventing HIV acquisition, opening a new venue for future design of HIV vaccines.

描述（由适用提供）：允许对艾滋病毒收购保护的保护的免疫效应机制仍然很少理解。最新数据来自Prime/Boost ALVAC+GP120蛋白疫苗的III期RV144试验，该试验的总体降低了病毒的总体降低31.2％，这表明抗GP120抗体反应的潜在受保护作用。具体而言，在RV144病例对照研究中评估的六个主要免疫学参数中，IgG对HIV Invelope GP120的V2回路的高反应与免受HIV感染的保护显着相关。但是，尚不清楚抗V2抗体是否具有阻断HIV感染的直接抗病毒功能。由于其高度可变序列，V2和GP120的其他可变环被认为是HIV疫苗的不良靶标。 While a closer scrutiny of V2 sequences has demonstrated a significant level of AA conservation including a conserved LDV/I motif, which is involved in binding ¿ 4¿7 integrin, the gut homing receptor expressed on key CD4 T cell targets for mucosal transmission, anti-V2 antibodies have little or no neutralizing activities against many HIV-1 primary isolates when measured under conventional assay conditions and with target cells expressing no ¿ 4¿7.我们在此提议利用非惯性的体外和体内方法研究抗V2抗体阻断HIV传播的能力。我们将首先测量抗V2人单克隆抗体在体外通过不同的孵育时间，温度，靶标CD4 T细胞阻断病毒感染的能力，具有或不具有活性的4€7，无细胞和细胞向细胞传输。其次，我们将测试体内人类抗V2单克隆抗体，以减少人源性小鼠中被动转移和病毒挑战中的HIV获取能力。最后，我们将评估通过疫苗接种而在体外和体内介导病毒促进的多克隆抗V2抗体。我们的结果将定义抗V2抗体反应在防止艾滋病毒收购方面的潜在贡献，为未来设计HIV疫苗的新场地开放。