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

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 由于 HIV 表现出广泛的抗原变异，HIV 疫苗的开发变得更加复杂。作为针对病毒的替代方案，我们开发了针对 CCR5 的疫苗，CCR5 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) 表面高密度展示源自 CCR5 的肽，我们证明可以有效克服 B 细胞耐受机制，该机制通常限制诱导针对自身蛋白的高滴度 IgG 抗体的能力。我们基于 VLP 的疫苗可诱导针对 CCR5 的高滴度 IgG 抗体，这些抗体与天然 CCR5 结合并抑制病毒复制。 在这个项目中，我们将评估基于VLP的针对CCR5的疫苗抑制猕猴粘膜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时的免疫原性。在目标 2 中，我们将通过阴道挑战方案挑战恒河猴，并评估疫苗接种提供的保护作用。这些研究将使我们能够评估针对 CCR5 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. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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.