Mucosal immunity and rectal challenge

描述（申请人提供）：HIV感染与胃肠道、口腔黏膜等粘膜组织中记忆性CD4 T细胞的大量丢失有关。这些CD4 T细胞不仅是传播HIV感染的一个现成的靶细胞池，而且对于产生抗病毒CD8 T细胞反应来对抗先前暴露的和机会性病原体也至关重要。关于粘膜疫苗接种保护粘膜部位CD4 T细胞区室的能力的信息有限。最近的研究表明，全身疫苗接种诱导了与粘膜CD4 T细胞部分保护相关的次优粘膜免疫反应。考虑到粘膜免疫系统的高度区隔性，很有可能粘膜免疫接种比全身免疫接种在粘膜组织中诱导更强的免疫反应。本建议的总体目标是评估粘膜疫苗接种策略，以诱导粘膜的有效免疫反应。我们假设粘膜疫苗接种可以诱导有效的免疫反应，可以在攻击后更好地保护粘膜中的CD4 T细胞，这种保护将与更好的长期预后相关。我们建议使用恒河猴模型来验证这一假设。在具体目标1中，我们将确定系统启动/粘膜增强是否比系统增强更能显着增强粘膜免疫反应。在特定目标2中，我们将确定交替的粘膜疫苗接种途径是否能更好地在粘膜中诱导有效的免疫反应。在特定目标3中，我们建议用佐剂接种粘膜，以确定它是否可以增强粘膜中的免疫反应，从而更好地与保护相关。总的来说，这些研究将使我们能够描述疫苗诱导的粘膜免疫在保护粘膜CD4 T细胞室免受感染方面的作用，从而获得更好的长期结果。公共卫生相关性：艾滋病毒通过杀死它所感染的细胞而迅速引起免疫缺陷。保护这些细胞免受感染对于防止艾滋病毒感染的破坏性影响和继发感染的发生至关重要。本项目探讨粘膜疫苗接种在保护细胞免受HIV感染中的作用，从而导致更好的长期生存结果。这里提出的研究将有助于开发有效的艾滋病毒疫苗。

DESCRIPTION (provided by applicant): HIV infection is associated with massive loss of memory CD4 T cells in mucosal tissues such as the gastrointestinal and oral mucosa. These CD4 T cells not only serve as a pool of readily available target cells for propagating HIV infection but are also critical for the generation of anti-viral CD8 T cell responses against previously exposed and opportunistic pathogens. Limited information exists regarding the ability of mucosal vaccination to protect the CD4 T cell compartment in mucosal sites. Recent studies have demonstrated that systemic vaccination induced suboptimal mucosal immune responses that were associated with partial protection of the mucosal CD4 T cells. Given the highly compartmentalized nature of the mucosal immune system it is highly likely that mucosal vaccination can induce stronger immune responses in mucosal tissues than systemic vaccination. The overall objectives of this proposal are to evaluate mucosal vaccination strategies to induce potent immune responses in the mucosa. We hypothesize that mucosal vaccination can induce potent immune responses that can better protect the CD4 T cells in the mucosa after challenge, and this protection will correlate with better long-term outcome. We propose to test this hypothesis using the rhesus macaque model. In Specific aim 1 we will determine if systemic prime/mucosal boost can significantly amplify mucosal immune responses better than systemic boosting. In Specific aim 2 we will determine if alternate mucosal vaccination routes are better at inducing potent immune responses in the mucosa. In Specific aim 3 we propose to vaccinate mucosally with adjuvants to determine if it can potentiate immune responses in the mucosa that better correlate with protection. Overall these studies will allow us to delineate the role of vaccine induced mucosal immunity in protecting the mucosa CD4 T cell compartment from infection leading to better long-term outcome. PUBLIC HEALTH RELEVANCE: HIV causes immunodeficiency very rapidly by killing the cells it infects. Protecting these cells from infection is critical to prevent the devastating effect of HIV infection and the onset of secondary infections. This project explores the role of mucosal vaccination in protecting cells from getting infected with HIV thereby leading to a better long-term survival outcome. The studies proposed here will aid in the development of an effective vaccine against HIV.