Antibody Effector Function and Virology

抗体效应器功能和病毒学

• 批准号: 8516873
• 负责人: Cynthia Ann Derdeyn
• 金额: $ 54.17万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8516873
• 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; Genetic Variation; 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; 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 application, the only immune correlate of protection against mucosal challenge identified thus far is the GM-CSF mediated avidity of vaccine-elicited antibody binding to the envelope ofthe challenge virus. The mechanism for protection is unknown but suggests an important role for the humoral immune response. The goals of the Virology and Antibody Assay Core are therefore to investigate (i) a mechanism for GM-CSF-based antibody protection (Project One), (ii) novel strategies for promoting humoral immunity within the gut mucosa (Project Two), and (iii) vaccine and challenge induced antibody specificities (NHP Monoclonal Antibody Core). The Virology Core is central to these studies and will assess whether neutralizing and Fc-mediated antibody activities correlate with vaccine-induced protection. 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 antibodies are likely to be a critical component of a vaccine, to date no one has elicited Nabs that can mediate neutralization of genetically diverse viruses, a feature that is critical for protection of HlV-1 infected humans. Other nonneutralizing antibody activities have been associated with protection against acquisition 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 genetic 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.

在这项应用项目一中使用的DNA PRIME，MVA Boost模型中，到目前为止发现的唯一与黏膜攻击保护相关的免疫关联是GM-CSF介导的疫苗诱导的抗体与挑战病毒膜结合的亲和力。保护机制尚不清楚，但提示了体液免疫反应的重要作用。因此，病毒学和抗体分析核心的目标是研究(I)基于GM-CSF的抗体保护的机制(项目一)，(Ii)促进肠道粘膜内体液免疫的新策略(项目二)，以及(Iii)疫苗和攻击诱导的抗体特异性(NHP单抗核心)。病毒学核心是这些研究的核心，将评估中和和Fc介导的抗体活动是否与疫苗诱导的保护相关。我们将专注于粘膜分泌物和血浆中针对病毒蛋白Env和Gag的抗体。中和抗体成分通过与病毒粒子相关形式的Env结合并防止靶细胞感染来介导抗病毒活性。虽然中和抗体可能是疫苗的关键成分，但到目前为止，还没有人诱导出能够介导基因多样性病毒中和的NAB，这一特征对于保护感染HLV-1的人类至关重要。其他非中和抗体活性与预防感染和疾病进展有关。这些包括识别在受感染细胞表面表达的Env，导致该细胞的裂解(ADCC)，以及增强其他可能有助于病毒抑制的非裂解机制(ADCVI)。最后，HIV-1和SIV通过生殖器粘膜的传播与遗传瓶颈有关，因此我们将确定在接种疫苗和对照猴子中建立感染的变异的特征，以确定疫苗诱导的抗体是否对环境病毒施加了选择性压力。具体来说，病毒学核心将确定外周和粘膜中的抗体活性是否与疫苗接种后对阴道内攻击的免疫保护相关，并调查是否存在明显的筛选效应。