Ghosh Amrit Raj, Habib Rumi, Mishra Nitesh, Roark Ryan S, Akauliya Madhav, Albowaidey Ali A, Allen Joel D, Amereh Khaled, Avillion Gabriel, Bottermann Maria, Liang Bo, Chaudhary Namit, Callaghan Sean, Dye Jonathan, Li Xuduo, Ellis-Pugh Jordan R, Chowdhury Rohan Roy, James Nicole E, Liu Xiaotie, Maiorino Laura, Maldonado Paula, Nedellec Rebecca, Oberoi Prabhgun, Sowers Kirsten J, Park Younghoon, Prum Thavaleak, Rodriguez Linette, Ssozi Maria, Torres Jon, Walsh Agnes A, Warner John E, Weldon Stephanie R, Xu Liling, Wiehe Kevin, Crispin Max, Ward Andrew B, Nair Usha, Hahn Beatrice H, Burton Dennis R, Shapiro Lawrence, Kwong Peter D, Irvine Darrell J, Andrabi Raiees, Shaw George M, Batista Facundo D
Ragon Institute of Mass General, MIT, and Harvard, Cambridge, MA, 02139, USA.
Departments of Medicine and Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
bioRxiv. 2025 Jun 17:2025.06.12.659380. doi: 10.1101/2025.06.12.659380.
Current vaccine strategies to elicit broadly neutralizing antibodies (bnAbs) against HIV-1 generally propose complex, multi-boost immunization regimens. In rhesus macaques, SHIV infection has been observed to rapidly drive the development of some classes of bnAbs that share structural similarities with those in humans. Here, we generated a knockin mouse model with B cells bearing the unmutated common ancestor (UCA) of the V2 apex-targeted bnAb lineage, V033-a. A single immunization of mice with a germline-targeting native-like trimer was sufficient to recapitulate the ontogeny of the mature rhesus bnAb in knockin mice-including rare, disfavored somatic mutations-leading to the induction of antibodies that exhibited potent neutralization against both autologous and heterologous tier 2 viruses. A boost with Env escape mutant trimers further improved breadth and potency, and cryo-EM structure revealed the structural basis for heterologous neutralization breadth. Non-human primate and mouse models can thus combine with structure to serve as a platform for identifying and confirming immunogens that streamline HIV-vaccination regimens.
目前旨在诱导针对HIV-1的广泛中和抗体（bnAbs）的疫苗策略通常采用复杂的多剂次免疫方案。在恒河猴中，已观察到感染SHIV会迅速推动某些类别的bnAbs的产生，这些bnAbs与人类中的bnAbs具有结构相似性。在此，我们构建了一种敲入小鼠模型，其B细胞携带靶向V2顶端的bnAb谱系V033-a的未突变共同祖先（UCA）。用靶向胚系的天然三聚体对小鼠进行单次免疫足以在敲入小鼠中重现成熟恒河猴bnAb的个体发生过程，包括罕见的、不利的体细胞突变，从而诱导出对同源和异源2级病毒均具有强效中和作用的抗体。用Env逃逸突变三聚体进行加强免疫进一步提高了中和广度和效力，冷冻电镜结构揭示了异源中和广度的结构基础。因此，非人类灵长类动物和小鼠模型可以与结构相结合，作为识别和确认简化HIV疫苗接种方案的免疫原的平台。
