Induction of autoantibodies against CCR5

描述（由申请人提供）：以产生中和抗体为基础的疫苗是有史以来最成功和最具成本效益的公共卫生干预措施之一，它们已被明确证明具有世界范围的适用性。该项目寻求使用基于疫苗诱导抗体的方法开发针对HIV-1共受体CCR5的进入抑制剂，CCR5在病毒复制和发病机制中起关键作用。我们之前已经证明，基于病毒样颗粒（VLP）的免疫原可以消除B细胞耐受的正常机制，并有效地诱导针对目标自身抗原（包括CCR5）的强体液免疫反应。在初步研究中，用CCR5偶联的VLPs免疫长尾猕猴，在体外产生了抗CCR5 IgG，可以阻断病毒的复制。在用ccr5 -热带SHIV病毒攻击后，与对照猕猴相比，接种疫苗的猕猴表现出更少的病毒载量和控制病毒血症的时间。我们现在建议使用小鼠模型更全面地评估ccrs -共轭VLPs诱导自身抗体的相关因素和效果。在具体目标1中，我们将测试不同佐剂和免疫方案的相容性，以及T在诱导小鼠高滴度全身和粘膜抗ccr5抗体反应中的作用。在特定目标2中，我们将使用体外实验和体内模型系统评估这些抗体对趋化因子功能的影响。在具体目标3中，我们将开发针对灵长类动物CCR5多个结构域的疫苗，并检测这些抗原诱导抗CCR5抗体抑制多种SIV和HIV分离株复制的能力。这些研究试图更充分地描述这种基于诱导针对CCR5（一种自身抗原）的抗体反应的新型免疫策略的潜力和风险。这些研究的最终目标是为HIV抗病毒药物库增加一种基于疫苗的方法。

DESCRIPTION (provided by applicant): Vaccines based on the production of neutralizing antibodies are among the most successful and cost effective public health interventions ever devised, and they have clearly been demonstrated to have worldwide applicability. This project seeks to use a vaccine induced antibody-based approach to develop entry-inhibitors targeting an HIV-1 coreceptor, CCR5, which plays a critical role in viral replication and pathogenesis. We have previously demonstrated that virus-like particle (VLP) based immunogens can abrogate the normal mechanisms of B cell tolerance and efficiently induce strong humoral immune responses against target self-antigens, including CCR5. In preliminary studies, pig-tailed macaques immunized with CCR5 conjugated VLPs made anti-CCR5 IgG which could block viral replication in vitro. Upon challenge with a CCR5-tropic SHIV virus, vaccinated macaques exhibited reduced viral loads and time to control of viremia relative to control macaques. We now propose to more fully evaluate the correlates and effects of autoantibody induction by CCRS-conjugated VLPs using a murine model. In specific aim 1, we will test the compatibility of different adjuvants and immunization regimens and the role of T help in the induction of high titer systemic and mucosal anti-CCR5 antibody responses in mice. In specific aim 2, we will assess the effects of these antibodies on chemokine function using in vitro assays and in vivo model systems. In specific aim 3, we will develop vaccines targeting multiple domains of primate CCR5 and examine the ability of these antigens to induce anti-CCR5 antibodies that inhibit the replication of diverse SIV and HIV isolates. These studies seek to more fully characterize both the potential and the risks of this novel immunization strategy, which is based on the induction of antibody responses against CCR5, a self-antigen. The ultimate goal of these studies is to add a vaccine-based approach to the arsenal of HIV anti-virals.