B-cell Biology of Mucosal Immune Protection from SIV Challenge

描述(由申请人提供)：开发一种安全有效的艾滋病毒-1疫苗对于遏制这种主要由性传播的疾病的传播至关重要，这种疾病目前正在全球影响3000多万人。虽然最近的一项痘病毒-蛋白质免疫原功效试验对感染提供了适度的保护，但保护的相关性尚不清楚。在恒河猴SIV感染模型中，经GM-CSF增强DNA免疫、MVA增强，然后接受异种(E660)、多次低剂量直肠攻击的猕猴中，高达70%的动物被保护而不被感染，保护作用与E660Env结合抗体亲和力明显相关。埃默里黏膜免疫保护B细胞生物学联盟将利用高度合作的方法，通过先进的免疫学和系统生物学方法，定义增强抗体亲和力和保护的潜在机制。该联盟将包括四个研究项目和四个科学支助核心，以及一个实现这一目标的行政核心。项目1将确定GM-CSF介导对低剂量SIV阴道攻击的增强保护的机制，并将确定添加优化的蛋白质Boost是否进一步增强保护。项目2将研究TLR-4和TLR-7配体在一种新的合成纳米颗粒配方中传递的潜在和潜在的机制，最近被证明可以显著提高对流感HA的抗体反应，以提高对SIV VLP的保护性粘膜B细胞和T细胞反应的质量。项目3将确定GM-CSF和纳米颗粒递送的TLR配体佐剂对滤泡T细胞的影响及其在塑造体液免疫反应质量方面的功能，而项目4将类似地研究这些佐剂方法激活具有B细胞辅助功能的IL-21产生的中性粒细胞亚群的可能性。这些项目将得到NHP核心的支持，该核心将为研究提供和维护具有基因特征的雌性猕猴。额外的核心将允许在单细胞和粘膜分泌物水平上表征抗病毒抗体反应，而B细胞生物标记物核心将开发独特的试剂来确定这个恒河猴模型中的B细胞反应。行政核心将通过数据库和储存库管理确保项目和核心之间的有效沟通和协作，并负责维持时间表、财政责任和传播研究成果。

DESCRIPTION (provided by applicant): The development of a safe and effective vaccine against HIV-1 is critical for curtailing the spread of a primarily sexually transmitted disease that is now affecting more than 30 million persons worldwide. While a recent poxvirus-protein immunogen efficacy trial conferred modest protection from acquisition, the correlates of protection are unknown. In the SIV infection model in Rhesus macaques, up to 70% of animals, vaccinated with GM-CSF enhanced DNA priming, MVA boosted, then subjected to a heterologous (E660), multiple low dose rectal challenge, were protected from acquisition and a clear correlate of protection was E660 Env binding antibody avidity. The Emory Consortium for B-Cell Biology of Mucosal Immune Protection from SIV Challenge, using highly collaborative approaches, will define through advanced immunological and systems biology approaches the underlying mechanisms for enhanced antibody avidity and protection. The Consortium will incorporate four research projects and four science support cores, in addition to an Administrative core to achieve this goal. Project 1 will identify the mechanisms by which GM-CSF mediates enhanced protection from low dose SIV vaginal challenge, and will determine whether addition of an optimized protein boost further enhances protection. Project 2 will investigate the potential and underlying mechanism for TLR-4 and TLR-7 ligands, delivered in a novel synthetic nanoparticle formulation and recently shown to dramatically improve antibody responses to influenza HA, to enhance the quality of protective mucosal B-cell and T-cell responses to SIV VLPs. Project 3 will determine the effects of GM-CSF and nanoparticle delivered TLR ligand adjuvants on follicular T-cells and their function in molding the quality of the humoral immune response, while Project 4 will similarly investigate the potential for these adjuvanting approaches to activate a subset of IL-21 producing N{BH} neutrophils equipped with B cell helper function. The projects will be supported by an NHP Core, which will provide and maintain genetically characterized female macaques for the studies. Additional Cores will allow characterization of the antiviral antibody response at the level of single cells and mucosal secretions, and a B-cell biomarker core will develop unique reagents for defining the B-cell response in this rhesus model. The Administrative Core will ensure effective communication and collaboration between projects and Cores through database and repository management and will be responsible for maintaining timelines, fiscal responsibility, and dissemination of research results.