Antibody Effector Function and Virology

抗体效应器功能和病毒学

• 批准号: 8326368
• 负责人: Cynthia Ann Derdeyn
• 金额: $ 53.37万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-07 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8326368
• 关键词: Antibodies; Antibody Formation; Antibody Specificity; Antigens; Antiviral Agents; Autologous; Avidity; B-Lymphocytes; Binding; Biological; Biological Assay; Cells; Cellular biology; Control Animal; Cytolysis; DNA; Disease Progression; Frequencies; Gagging; Genetic; Genital system; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; HIV-1; Human; Humoral Immunities; Immune; Immune response; Immunoglobulin A; Immunoglobulin G; Infection; Infection prevention; Instruction; Macaca; Measures; Mediating; Modeling; Molecular; Molecular Cloning; Monkeys; Monoclonal Antibodies; Mucous Membrane; Nature; Pathway interactions; Peripheral; Plasma; Plasmablast; Property; Role; SIV; Serum; Site; Specificity; Surface; System; Vaccinated; Vaccination; Vaccines; Vagina; Variant; Viral; Viral Envelope Proteins; Virion; Virus; antibody-dependent cell cytotoxicity; base; neutralizing antibody; novel strategies; pre-clinical; pressure; rectal; response; transmission process; virology; virus envelope

In the DNA prime, MVA boost model to be used in Project One of this applicafion, the only immune correlate of protection against mucosal challenge identified thus far is the GM-CSF mediated avidity of vaccine-elicited anfibody binding to the envelope ofthe challenge virus. The mechanism for protecfion is unknown but suggests an important role for the humoral immune response. The goals of the Virology and Anfibody Assay Core are therefore to investigate (i) a mechanism for GM-CSF-based antibody protection (Project One), (ii) novel strategies for promofing humoral immunity within the gut mucosa (Project Two), and (iii) vaccine and challenge induced anfibody specificities (NHP Monoclonal Anfibody Core). The Virology Core is central to these studies and will assess whether neutralizing and Fc-mediated anfibody acfivifies correlate with vaccine-induced protecfion. We will focus on antibodies within mucosal secretions and plasma against viral proteins Env and Gag. The neutralizing antibody component mediates antiviral activity by binding to the virion associated form of Env and preventing infection of a target cell. While neutralizing anfibodies are likely to be a critical component of a vaccine, to date no one has elicited Nabs that can mediate neutralizafion of genetically diverse viruses, a feature that is critical for protection of HlV-1 infected humans. Other nonneutralizing antibody acfivifies have been associated with protection against acquisifion and disease progression. These involve recognition ofthe Env expressed on the surface of an infected cell, leading to lysis of that cell (ADCC) in addition to augmenting other non-lytic mechanisms that may contribute to viral suppression (ADCVI). Finally, transmission of HIV-1 and SIV across the genital mucosa is associated with a genefic bottleneck, and we will therefore characterize the variants that establish infection in the vaccinated and control monkeys to determine whether vaccine-induced antibodies imposed selective pressure on Env. Specifically, the Virology Core will determine whether peripheral and mucosal IgG and IgA-mediated antibody activities correlate with immune protection against intravaginal challenge following vaccination and investigate whether a sieve effect is evident.

在DNA初免中，将在该应用程序的项目一中使用的MVA加强模型是唯一的免疫相关物 迄今为止确定的对粘膜攻击的保护作用是GM-CSF介导的疫苗引起的免疫应答的亲合力。 抗体与攻击病毒的包膜结合。其保护机制尚不清楚， 提示了体液免疫应答的重要作用。病毒学和Anfibody检测的目的 因此，核心是研究（i）基于GM-CSF的抗体保护机制（项目一），（ii） 用于促进肠粘膜内的体液免疫的新策略（项目二），和（iii）疫苗和 攻击诱导的抗体特异性（NHP单克隆抗体核心）。病毒学核心是 这些研究将评估中和和Fc介导的抗体活化是否与 疫苗诱导的保护作用。我们将重点关注粘膜分泌物和血浆中抗病毒的抗体 蛋白Env和Gag。中和抗体组分通过结合抗病毒抗体介导抗病毒活性。 病毒体相关形式的Env并防止靶细胞感染。虽然中和抗体很可能 作为疫苗的关键组分，迄今为止还没有人诱导出可以介导中和 遗传多样性病毒，这是保护HIV-1感染的人的关键特征。其他非中和 抗体活性与预防获得性免疫和疾病有关， 进展这些包括识别在感染细胞表面表达的Env，导致 细胞裂解（ADCC）除了增强可能导致病毒感染的其他非裂解机制外， 抑制（ADCVI）。最后，HIV-1和SIV通过生殖器粘膜的传播与生殖器粘膜的感染有关。 基因瓶颈，因此，我们将描述在接种疫苗的人中建立感染的变异。 和对照猴，以确定疫苗诱导的抗体是否对Env施加选择性压力。 具体而言，病毒学核心将确定外周和粘膜IgG和IgA介导的 抗体活性与疫苗接种后针对阴道内攻击的免疫保护相关， 研究筛选效应是否明显。