EVALUATION OF A CCR5 VACCINE FOR HIV INFECTION IN THE SIV/MACAQUE MODEL

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 HIV疫苗的开发由于广泛的抗原变异而变得复杂 艾滋病毒显示。作为靶向病毒的替代方案，我们已经开发了靶向CCR 5的疫苗，CCR 5是一种与HIV复制、传播和发病机制密切相关的自身蛋白。通过在病毒样颗粒（VLP）的表面上以高密度展示源自CCR 5的肽，我们已经表明我们可以有效地克服通常限制诱导针对自身蛋白的高滴度IgG抗体的能力的B细胞耐受性的机制。我们的基于VLP的疫苗诱导针对CCR 5的高滴度IgG抗体，这些抗体结合天然CCR 5并抑制病毒复制。 在这个项目中，我们将评估以CCR 5为靶点的VLP疫苗抑制猕猴粘膜SIV感染的能力。在目标1中，我们将评估我们的疫苗在肌肉内和阴道内接种后的免疫原性。在目标2中，我们将通过阴道攻击方案攻击恒河猴，并评估疫苗接种提供的保护。这些研究将使我们能够评估针对CCR 5的疫苗预防HIV感染的潜力。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. HIV vaccine development has been complicated by the extensive antigenic variation displayed by HIV. As an alternative to targeting the virus, we have developed vaccines targeting CCR5, a selfprotein that is critically involved in HIV replication, transmission, and pathogenesis. By displaying peptides derived from CCR5 at high density on the surface of virus-like particles (VLPs), we have shown that we can efficiently overcome the mechanisms of B cell tolerance that normally limit the ability to induce high-titer IgG antibodies against self-proteins. Our VLP-based vaccines induce hightiter IgG antibodies against CCR5, these antibodies bind to native CCR5 and inhibit viral replication. In this project, we will evaluate the ability of a VLP-based vaccine targeting CCR5 to inhibit mucosal SIV infection of macaques. In Aim 1 we will evaluate the immunogenicity of our vaccines upon intramuscular and intravaginal inoculation. In Aim 2 we will challenge rhesus macaques via a vaginal challenge protocol and assess the protection provided by vaccination. These studies will allow us to assess the potential of vaccines targeting CCR5 to protect against HIV infection.