Innate/ SIV DNA vaccine induced immunity in the protected macaque mucosa

描述(由申请人提供)： 最近的一份报告称，ALVAC-HIV Prime：gp120蛋白(AIDSVAX B/E)的增强已经在一小部分但数量可观的参与者中预防了感染，这为预防HIV性传播的疫苗提供了希望。这项研究得到了在SIV：猕猴艾滋病模型中评估的其他疫苗的结果的支持，包括我们自己使用的颗粒介导的表皮递送(PMEd)DNA疫苗。该疫苗预防了40%的直肠内注射高剂量异源初级SIV分离株的疫苗接种者的感染，从而证明了SIV：猕猴模型中观察到的粘膜保护的免疫相关性将在人类中模拟粘膜保护。使用我们团队开发的黏膜模型，可以重复采集接种疫苗的猕猴的GALT，我们将确定PMEd DNA疫苗诱导的粘膜保护性免疫反应的关键成分。我们将检验以下假设：(1)疫苗提供保护不是通过预防感染，而是通过阻止病毒从粘膜隔间逃逸；(2)宿主对病毒感染的反应必须出现在进入粘膜的入口，以防止性传播--这是一种需要对粘膜组织进行直接分析的条件；(3)适当地启动和/或召回粘膜中的病毒特异性保护性免疫的能力是调节病毒复制和/或组成粘膜固有免疫系统的防御素/趋化因子的表达的个体的固有属性；(4)诱导具有识别粘膜组织中广泛表位的效应记忆T细胞表型的病毒特异性多功能T细胞是粘膜保护所必需的；(5)PMEd DNA疫苗通过诱导定位于粘膜间隔的高亲和力T细胞克隆来增加肠道内T细胞反应的广度。我们将在以下目标中解决这些假设：目标1：Martinson和Reinhart博士将通过量化GALT中的表达并确定受保护动物和未受保护动物的相关多态性，直接确定宿主特异性的粘膜相关防御素和趋化因子的表达与疫苗介导的保护的关系。目的2：富勒博士将确定黏膜保护的获得性免疫相关因素，并确定它们与先天免疫的关系。目的3：Murphey-Corb博士将确定粘膜病毒负荷和逃逸、先天和适应性反应以及PMEd DNA疫苗诱导的保护之间的三方相互作用。总之，这些研究将确定增强疫苗诱导的保护性免疫的新方法，并揭示重复低剂量(性)暴露对疫苗预防的影响。这个应用程序的目的是确定由于性接触艾滋病毒而发生的分子事件，以便我们可以更好地了解为什么有些人会感染，而另一些人没有。了解最初接触地点发生的情况与开发能够防止艾滋病毒性传播的疫苗高度相关。

DESCRIPTION (provided by applicant): The recent report that the ALVAC-HIV prime: gp120 protein (AIDSVAX B/E) boost has prevented infection in a small, but significant number of participants, provides hope that a vaccine that can prevent HIV sexual transmission is possible. This study is supported by results with other vaccines evaluated in the SIV:macaque model for AIDS, including our own using a particle mediated epidermal delivery (PMED) DNA vaccine. This vaccine prevented infection in 40% of vaccinates challenged intrarectally with a high dose of a heterologous primary SIV isolate, thereby demonstrating that immune correlates of mucosal protection observed in the SIV:macaque model will mimic mucosal protection in humans. Using a mucosal model developed by our group that enables repetitive sampling of the GALT in vaccinated macaques, we will identify the critical components of the mucosal protective immune response induced by the PMED DNA vaccine. We will test the following hypotheses: (1) A vaccine confers protection not by preventing infection but by blocking virus escape from the mucosal compartment; (2) The host response to viral infection must be present at the mucosal portal of entry to prevent sexual transmission - a condition requiring direct analysis of the mucosal tissues; (3) The ability to appropriately prime and/or recall virus-specific protective immunity in the mucosa are intrinsic propert(ies) of the individual that modulate either virus replication and/or expression of defensins/chemokines comprising the mucosal innate immune system; (4) The induction of virus-specific poly-functional T cells with an effector memory T-cell phenotype recognizing a broad repertoire of epitopes in the mucosal tissues is required for mucosal protection; (5) A PMED DNA vaccine increases the breadth of the T cell responses in the gut by induction of high-avidity T cell clones that localize to the mucosal compartment. We will address these hypotheses in the following aims: Aim 1: Drs. Martinson and Reinhart will directly determine the relationship of host-specific expression of mucosally relevant defensins and chemokines to vaccine-mediated protection by quantifying expression in the GALT and identifying related polymorphisms in protected and unprotected animals. Aim 2: Dr. Fuller will identify adaptive immune correlates of protection in the mucosa and determine their relationship to innate immunity. Aim 3: Dr. Murphey-Corb will determine the tripartite interplay among mucosal virus burden and escape, innate and adaptive responses, and protection induced by the PMED DNA vaccine. Together, these studies will identify novel approaches to enhance vaccine-induced protective immunity and reveal the impact of repetitive low dose (sexual) exposure on vaccine prevention. The objective of this application is to determine the molecular events that occur as a result of sexual exposure to HIV so that we may better understand why some people get infected while others do not. Understanding just what occurs at the site of initial exposure is highly relevant to the development of a vaccine that can prevent sexual transmission of HIV.