Induction of autoantibodies against CCR5

基于生产中和抗体的疫苗是最成功和最昂贵的疫苗之一。 曾经设计过的有效的公共卫生干预措施，而且它们显然已经被证明具有 在全球范围内适用。该项目寻求使用疫苗诱导抗体为基础的方法来开发 针对HIV-1辅助受体CCR5的进入抑制剂，CCR5在病毒复制和 发病机制。我们之前已经证明了基于病毒样颗粒(VLP)的免疫原可以 消除正常的B细胞耐受机制，有效诱导强大的体液免疫 对目标自身抗原的反应，包括CCR5。在初步研究中，猪尾猕猴 CCR5偶联VLP免疫小鼠后，可在体外获得能阻断病毒复制的抗CCR5抗体。 在与CCR5嗜性新城疫病毒的攻击中，接种疫苗的猕猴表现出更少的病毒载量和时间 相对于控制猕猴，控制病毒血症。我们现在建议更全面地评估相关因素和 用小鼠模型研究CCRs偶联VLP诱导自身抗体的效果。在具体目标1中，我们将 检测不同佐剂和免疫方案的配伍性以及T Help在诱导中的作用 高滴度的小鼠全身和粘膜抗CCR5抗体反应。在具体目标2中，我们将评估 使用体外分析和体内模型系统研究这些抗体对趋化因子功能的影响。在……里面 具体目标3，我们将开发针对灵长类CCR5多个结构域的疫苗并检测其能力 诱导抗CCR5抗体，从而抑制不同的SIV和HIV分离株的复制。 这些研究试图更全面地描述这种新型免疫的潜在和风险。 策略，其基础是诱导针对CCR5的抗体反应，CCR5是一种自身抗原。终极的 这些研究的目标是在艾滋病毒抗病毒药物库中增加一种基于疫苗的方法。

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-conjugatedVLPs 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.