Longitudinal analysis of antibody responses to HIV-1:mapping function to genotype

描述(申请人提供)：到目前为止，还没有针对人类免疫缺陷病毒(HIV)的疫苗接种策略取得广泛成功。艾滋病毒已经发展出通过高变异率逃避体液反应的机制。在HIV-1感染者的一个子集中，已经产生了广泛的中和抗体(BNAbs)。这些强大的抗体针对跨多个分支的病毒包膜上保留的表位。一个可行的疫苗接种策略可能需要确定bNAbs在暴露于免疫原时进化的机制。这项建议涉及以下两个问题：1)HIV-1感染者的抗体库是如何随着时间的推移而演变的？2)对HIV-1的功能性抗体反应如何与进化阶段相关？这些问题将在目标1)中解决，该目标建议对HIV-1感染者的纵向B细胞库进行深度测序，使用这些序列组装系统发育树，描述具有广泛中和活性和较差中和活性的个体中抗体库的不同进化。Aim 2)建议对Aim 1中深度测序的相同谱系中的单个B细胞进行功能性抗体表型筛选。这些功能表型信息将与系统发育图相关联，以识别bNAbs及其克隆祖先。这将提供对bNAb如何自然进化的机制的洞察。我们的结果将有助于制定HIV-1疫苗接种战略，为诱导bNAbs提供蓝图。

DESCRIPTION (provided by applicant): To date no vaccination strategy against Human Immunodeficiency Virus (HIV) has been widely successful. HIV has developed mechanisms to escape the humoral response through a high mutation rate. In a subset of HIV-1 infected individuals, broadly neutralizing antibodies (bNAbs) have developed. These potent antibodies target preserved epitopes on the viral envelope across multiple clades. A viable vaccination strategy likely necessitates determining the mechanisms by which bNAbs evolve upon exposure to immunogens. The following two questions are addressed in this proposal: 1) How does the antibody repertoire evolve in HIV-1 infected individuals over time? 2) How does the functional antibody response to HIV-1 correlate to evolutionary stage? These questions will be addressed in Aim 1) which proposes to deep sequence longitudinal B-cell repertoires from HIV-1 infected individuals, using the sequences to assemble a phylogenetic tree depicting the divergent evolution of the antibody repertoires in individuals with broadly versus poorly neutralizing activity. Aim 2) proposes to perform a functional antibody phenotype screen of single B-cells from the same repertoires deep sequenced in Aim 1. The functional phenotype information will be linked to the phylogenetic map to identify bNAbs and their clonal ancestors. This will provide insight into the mechanisms of how bNAbs naturally evolve. Our results will contribute to the development of HIV-1 vaccination strategies by providing a blueprint for the elicitation of bNAbs.