Antibody Effector Function and Virology

在本应用项目1中使用的DNA引物、MVA增强模型中，迄今为止确定的对抗粘膜攻击的唯一免疫关联是GM-CSF介导的疫苗诱导抗体与攻击病毒包膜结合的亲和力。其保护机制尚不清楚，但提示其在体液免疫应答中起重要作用。因此，病毒学和抗体分析核心的目标是研究(i)基于gm - csf的抗体保护机制（项目一），（ii）促进肠道粘膜体液免疫的新策略（项目二），以及（iii）疫苗和挑战诱导抗体特异性（NHP单克隆抗体核心）。病毒学核心是这些研究的核心，将评估中和和fc介导的抗体活性是否与疫苗诱导的保护相关。我们将重点关注粘膜分泌物和血浆中针对病毒蛋白Env和Gag的抗体。中和抗体成分通过结合Env的病毒粒子相关形式和防止靶细胞的感染来介导抗病毒活性。虽然中和抗体可能是疫苗的关键组成部分，但迄今为止还没有人诱导出能够介导遗传多样性病毒中和的nab，而这一特征对于保护受HlV-1感染的人类至关重要。其他非中和抗体活性与预防获得性和疾病进展有关。这包括对受感染细胞表面表达的Env的识别，导致该细胞的裂解（ADCC），以及增加其他可能有助于病毒抑制（ADCVI）的非裂解机制。最后，HIV-1和SIV在生殖器粘膜上的传播与遗传瓶颈有关，因此，我们将表征在接种疫苗和对照猴子中建立感染的变异，以确定疫苗诱导的抗体是否对Env施加了选择性压力。具体而言，病毒学核心将确定外周和粘膜IgG和iga介导的抗体活性是否与疫苗接种后对阴道内攻击的免疫保护相关，并研究筛孔效应是否明显。

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.