Mucosal Protection Against HIV Generated by PIV5 Priming and VLP Boosting

描述(由申请人提供)：需要新的方法来开发预防艾滋病毒感染的有效疫苗。设计有效疫苗所面临的主要挑战之一是病毒的遗传变异性及其一旦在受感染宿主内传播后迅速逃避免疫反应的能力。艾滋病毒最常见的感染途径是通过性接触接触粘膜。对猕猴和人类的研究表明，SIV或HIV最初在粘膜组织中局部复制，然后通过血液传播到全身的淋巴组织。在局部粘膜部位暴露后的早期事件中起作用的疫苗在限制或防止病毒复制和随后的传播方面可能更有效。这项应用将采取一种方法，通过接种表达SIV Gag和HIV Env的5型副流感病毒(PIV5)载体和通过黏膜应用Gag-Env病毒样颗粒(VLP)来激发局部粘膜免疫反应。PIV5以前没有被评估为HIV候选疫苗，由于其在粘膜上的应用和已证明的在粘膜部位保护其他病原体的能力而具有吸引力。这项提议中的实验将确定在小鼠和 猕猴。在PIV5黏膜免疫和VLP直肠或肌肉增强免疫后，将在猕猴身上进行低剂量直肠内攻击实验。这些实验将确定旨在刺激直肠黏膜局部强烈反应的载体是否对SHIV感染具有保护作用，并将寻求确定粘膜免疫保护的相关因素。

DESCRIPTION (provided by applicant): New approaches are needed to develop an effective vaccine for the prevention of HIV infection. Among the major challenges faced in designing an effective vaccine is the genetic variability of the virus and its ability to rapidly escape immune responses once it has disseminated within the infected host. HIV is most frequently acquired via mucosal exposure through sexual contact. Studies in macaques and humans have shown that SIV or HIV initially replicates locally in mucosal tissues prior to disseminating to lymphoid tissues throughout the body through the bloodstream. A vaccine that acts during early events following exposure at the local mucosal site may be more effective in limiting or preventing virus replication and subsequent dissemination. This application will take an approach to eliciting local mucosal immune responses through vaccination with parainfluenza virus type 5 (PIV5) vectors expressing SIV Gag and HIV Env and through mucosal application of Gag-Env virus-like particles (VLPs) engineered to reach the rectal mucosa-associated lymphoid tissue. PIV5 has not previously been evaluated as an HIV vaccine candidate, and is attractive due to its mucosal application and proven ability to protect at mucosal sites for other pathogens. Experiments in this proposal will define the ideal route to elicit potent intrarectal immune responses in mice and macaques. A low-dose intrarectal challenge experiment will be performed in macaques following mucosal immunization with PIV5 and rectal or intramuscular boosting with VLPs. These experiments will determine if vectors designed to stimulate potent local response in the rectal mucosa are protective from SHIV infection, and will seek to define correlates of mucosal immune protection.