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：
8673508
负责人：
Catarina E Hioe
金额：
$ 29.6万
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：
2013
资助国家：
美国
起止时间：
2013-08-19 至 2014-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8673508
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

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 ¿4B7 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 ¿4B7. 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 ¿4B7, 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.

免疫效应机制对于防止 HIV 感染的机制仍知之甚少，而 ALVAC+gp120 蛋白疫苗的 III 期 RV144 试验的最新数据表明，该疫苗的病毒感染率总体降低了 31.2%，这表明抗 HIV 疫苗的潜在保护作用。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，对 HIV 包膜 gp120 V2 环的高 IgG 反应与保护显着相关。然而，目前尚不清楚抗 V2 抗体是否具有阻断 HIV 感染的直接抗病毒功能，而 gp120 的其他可变环由于其高度可变的序列而被认为是 HIV 疫苗的不良目标。对 V2 序列的仔细检查表明，AA 具有显着的保守性，包括保守的 LDV/I 基序，该基序参与结合 ¿ 4B7 整合素是在粘膜传播的关键 CD4 T 细胞靶标上表达的肠道归巢受体，在常规检测条件下测量且靶细胞不表达 ¿ 4B7. 我们建议利用非常规的体外和体内方法来研究抗 V2 抗体阻止 HIV 传播的能力。我们将首先通过以下方法测量抗 V2 人单克隆抗体在体外阻止病毒感染的能力。不同的孵育时间、温度、有或没有活性的靶 CD4 T 细胞 ¿ 4B7，无细胞和细胞间传播其次，我们将在体内测试人抗V2单克隆抗体在人源化小鼠中减少被动传播和病毒攻击中HIV感染的能力。通过疫苗接种产生的多克隆抗 V2 抗体在体外和体内介导病毒阻断，我们的结果将确定抗 V2 抗体反应在预防 HIV 感染方面的潜在贡献，为未来的 HIV 疫苗设计开辟了新的领域。