Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC, USA.
Department of Medicine, Duke University Medical Center, Durham, NC, USA.
Nat Commun. 2024 Nov 3;15(1):9503. doi: 10.1038/s41467-024-53120-9.
Vaccine development targeting rapidly evolving pathogens such as HIV-1 requires induction of broadly neutralizing antibodies (bnAbs) with conserved paratopes and mutations, and in some cases, the same Ig-heavy chains. The current trial-and-error search for immunogen modifications that improve selection for specific bnAb mutations is imprecise. Here, to precisely engineer bnAb boosting immunogens, we use molecular dynamics simulations to examine encounter states that form when antibodies collide with the HIV-1 Envelope (Env). By mapping how bnAbs use encounter states to find their bound states, we identify Env mutations predicted to select for specific antibody mutations in two HIV-1 bnAb B cell lineages. The Env mutations encode antibody affinity gains and select for desired antibody mutations in vivo. These results demonstrate proof-of-concept that Env immunogens can be designed to directly select for specific antibody mutations at residue-level precision by vaccination, thus demonstrating the feasibility of sequential bnAb-inducing HIV-1 vaccine design.
针对 HIV-1 等快速进化病原体的疫苗开发需要诱导具有保守表位和突变的广泛中和抗体（bnAb），在某些情况下，还需要相同的重链免疫球蛋白。目前，针对免疫原修饰的反复试验搜索，以改善针对特定 bnAb 突变的选择并不精确。在这里，为了精确设计 bnAb 增强免疫原，我们使用分子动力学模拟来研究当抗体与 HIV-1 包膜（Env）碰撞时形成的接触状态。通过映射 bnAb 如何使用接触状态来找到它们的结合状态，我们确定了 HIV-1 两种 bnAb B 细胞谱系中预测会选择特定抗体突变的 Env 突变。这些抗体突变编码抗体亲和力的提高，并在体内选择所需的抗体突变。这些结果证明了一个概念验证，即通过疫苗接种，Env 免疫原可以设计为直接在残基水平上精确选择特定的抗体突变，从而展示了基于 bnAb 的 HIV-1 疫苗设计的可行性。
