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HIV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中传播就迅速逃避免疫反应的能力。艾滋病毒最常通过性接触的粘膜接触获得。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，然后通过血流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期间起作用的疫苗可能更有效地限制或预防病毒复制和随后的传播。本申请将采用通过用表达SIV Gag和HIV Env的5型副流感病毒（PIV 5）载体接种疫苗以及通过粘膜应用经工程改造以到达直肠粘膜相关淋巴组织的Gag-Env病毒样颗粒（VLP）来引发局部粘膜免疫应答的方法。PIV 5以前未被评估为HIV候选疫苗，由于其粘膜应用和已证实的在粘膜部位保护其他病原体的能力而具有吸引力。该提案中的实验将确定引发小鼠有效直肠内免疫应答的理想途径， 猕猴在用PIV 5粘膜免疫和用VLP直肠或肌内加强免疫后，将在猕猴中进行低剂量直肠内攻毒实验。这些实验将确定设计用于刺激直肠粘膜中的有效局部应答的载体是否对SHIV感染具有保护作用，并将寻求确定粘膜免疫保护的相关性。

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.