Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
Los Alamos National Laboratory, Los Alamos, NM 87545, USA; New Mexico Consortium, Los Alamos, NM 87545, USA.
Cell Host Microbe. 2019 Jan 9;25(1):59-72.e8. doi: 10.1016/j.chom.2018.12.001.
Eliciting HIV-1-specific broadly neutralizing antibodies (bNAbs) remains a challenge for vaccine development, and the potential of passively delivered bNAbs for prophylaxis and therapeutics is being explored. We used neutralization data from four large virus panels to comprehensively map viral signatures associated with bNAb sensitivity, including amino acids, hypervariable region characteristics, and clade effects across four different classes of bNAbs. The bNAb signatures defined for the variable loop 2 (V2) epitope region of HIV-1 Env were then employed to inform immunogen design in a proof-of-concept exploration of signature-based epitope targeted (SET) vaccines. V2 bNAb signature-guided mutations were introduced into Env 459C to create a trivalent vaccine, and immunization of guinea pigs with V2-SET vaccines resulted in increased breadth of NAb responses compared with Env 459C alone. These data demonstrate that bNAb signatures can be utilized to engineer HIV-1 Env vaccine immunogens capable of eliciting antibody responses with greater neutralization breadth.
诱导 HIV-1 特异性广泛中和抗体（bnAbs）仍然是疫苗开发的一个挑战，被动给予 bnAbs 用于预防和治疗的潜力正在被探索。我们使用来自四个大型病毒面板的中和数据，全面绘制与 bnAb 敏感性相关的病毒特征图谱，包括氨基酸、高变区特征和四个不同类别 bnAb 的谱系效应。然后，将针对 HIV-1 Env 的可变环 2（V2）表位区域定义的 bnAb 特征用于信息免疫原设计，以探索基于特征的表位靶向（SET）疫苗。将 V2 bnAb 特征指导的突变引入Env 459C 中，构建了一种三价疫苗，用 V2-SET 疫苗免疫豚鼠可导致比单独使用 Env 459C 时更大的 NAb 反应广度。这些数据表明，bnAb 特征可用于设计 HIV-1Env 疫苗免疫原，这些免疫原能够诱导具有更大中和广度的抗体反应。
