Mucosal immunity and rectal challenge

描述(申请人提供)：HIV感染与胃肠道和口腔黏膜等粘膜组织中的大量记忆丧失有关。这些CD4T细胞不仅是传播HIV感染的现成靶细胞，而且对于产生抗病毒CD8T细胞对先前暴露的和机会性的病原体也是至关重要的。关于粘膜免疫保护粘膜部位的CD4T细胞的能力，目前存在有限的信息。最近的研究表明，系统免疫诱导了次优的粘膜免疫反应，这与粘膜CD4T细胞的部分保护有关。鉴于黏膜免疫系统高度区隔的性质，黏膜免疫接种极有可能比全身免疫在黏膜组织中诱导更强的免疫反应。这项建议的总体目标是评估粘膜疫苗接种策略，以在粘膜中诱导强大的免疫反应。我们假设黏膜疫苗接种可以诱导强大的免疫反应，在攻击后能更好地保护粘膜中的CD4T细胞，这种保护将与更好的长期结果相关。我们建议使用恒河猴模型来检验这一假设。在特定的目标1中，我们将确定系统基础/粘膜增强是否能显著增强黏膜免疫反应，比系统增强效果更好。在特定的目标2中，我们将确定替代的粘膜接种途径是否在粘膜中诱导强大的免疫反应方面更好。在特定的目标3中，我们建议用粘膜佐剂进行免疫接种，以确定它是否可以增强粘膜中与保护更相关的免疫反应。总体而言，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CD4T细胞隔间免受感染方面的作用，从而获得更好的长期结果。与公共卫生相关：艾滋病毒通过杀死其感染的细胞，非常迅速地导致免疫缺陷。保护这些细胞不受感染对于防止艾滋病毒感染和继发感染的破坏性影响至关重要。这个项目探索了粘膜疫苗在保护细胞免受艾滋病毒感染方面的作用，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.