Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 17177 Stockholm, Sweden.
J Immunol. 2013 Jul 1;191(1):44-51. doi: 10.4049/jimmunol.1203087. Epub 2013 Jun 5.
Abs that bind the functional envelope glycoprotein (Env) spike are considered critical for a broadly effective prophylactic HIV-1 vaccine. The difficulty in eliciting such Abs by vaccination is partially attributed to the immunodominance of hydrophilic, surface-exposed variable protein regions of Env. However, little is known about the potential for competition between B cells that recognize distinct and distal epitopes on Env during protein subunit vaccination. In this study, we address this basic question at the level of Ab-secreting cells and serum IgG using a pair of isogenic soluble Env trimers, designated wildtype and gV3, which differ only in their potential to activate B cell responses against the highly immunogenic V3 region of Env. Immunization of mice with gV3 resulted in a markedly lower Ag-specific response compared with that induced by wildtype Env and could be explained by a loss of V3-directed reactivities. There was no redistribution of the response to other regions of Env in gV3-inoculated mice, suggesting that the epitope-specific Ab-secreting cell responses measured after boost are independently regulated rather than dictated by direct or indirect competition between B cells recognizing different structural elements of Env. This information is relevant for ongoing efforts in Env immunogen design to focus responses on conserved neutralizing determinants and for our general understanding of B cell responses to large-protein Ags that display numerous B cell epitopes.
能够结合功能性包膜糖蛋白（Env）刺突的 Abs 被认为是广泛有效的预防性 HIV-1 疫苗的关键。通过疫苗接种来引发这种 Abs 的困难部分归因于 Env 的亲水、表面暴露的可变蛋白区域的免疫优势。然而，对于在蛋白亚单位疫苗接种过程中识别 Env 上不同且远端表位的 B 细胞之间潜在的竞争知之甚少。在这项研究中，我们使用一对同源可溶性 Env 三聚体来解决这个基本问题，这些三聚体分别命名为野生型和 gV3，它们仅在激活针对 Env 高度免疫原性 V3 区域的 B 细胞反应的能力上有所不同。用 gV3 免疫小鼠会导致明显低于野生型 Env 诱导的 Ag 特异性反应，这可以用 V3 定向反应的丧失来解释。在 gV3 接种的小鼠中，没有向 Env 的其他区域重新分配反应，这表明在加强后测量的针对特定表位的 Ab 分泌细胞反应是独立调节的，而不是由识别 Env 不同结构元件的 B 细胞之间的直接或间接竞争决定的。这些信息对于正在进行的 Env 免疫原设计工作将反应集中在保守的中和决定簇上，以及我们对显示大量 B 细胞表位的大蛋白 Ag 的 B 细胞反应的一般理解是相关的。
