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 Prime中，MVA增强模型将用于该应用程序之一，这是唯一的免疫相关性 迄今为止确定的防止粘膜挑战的保护是GM-CSF介导的疫苗吸收的亲戚 Anfiboty与挑战病毒的包膜结合。 protecfion的机制尚不清楚，但 提出了体液免疫反应的重要作用。病毒学和脂肪纤维测定的目标 因此，核心将研究（i）基于GM-CSF的抗体保护的机制（项目一），（ii） 肠粘膜（项目第二）和（iii）疫苗和（III）和（III）和（III）和（III）和 挑战诱导的脱纤维特异性（NHP单克隆脱纤维核心）。病毒学核心是 这些研究并将评估中和和FC介导的弧形分解是否与 疫苗诱导的蛋白质。我们将专注于粘膜分泌物中的抗体和针对病毒的血浆 蛋白质环境和插科打。中和抗体成分通过与 Ever与Env相关的形式，并防止靶细胞感染。而中和亚纤维可能是 要成为疫苗的关键成分，迄今 遗传多样的病毒，这对于保护HLV-1感染的人至关重要。其他非中和 抗体助剂与免征和疾病的保护有关 进展。这些涉及对感染细胞表面表达的Env的识别，导致 该细胞（ADCC）的裂解外，还增加了可能导致病毒的其他非灯笼机制 抑制（ADCVI）。最后，HIV-1和SIV在生殖器粘膜中的传播与 Genefic瓶颈，因此我们将表征在接种疫苗中建立感染的变体 并控制猴子，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的免疫保护抗体挑战相关， 调查筛子是否明显。