Dam Kim-Marie A, Gristick Harry B, Li Yancheng E, Yang Zhi, Gnanapragasam Priyanthi N P, West Anthony P, Seaman Michael S, Bjorkman Pamela J
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA; Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
Cell Rep. 2025 May 27;44(5):115713. doi: 10.1016/j.celrep.2025.115713. Epub 2025 May 15.
HIV-1 broadly neutralizing antibodies (bNAbs) targeting the CD4-binding site (CD4bs) contain rare features that pose challenges to elicit these bNAbs through vaccination. The IOMA class of CD4bs bNAbs includes fewer rare features and somatic hypermutations (SHMs) to achieve broad neutralization, thus presenting a potentially accessible pathway for vaccine-induced bNAb development. Here, we created a library of IOMA variants in which each SHM was individually reverted to the inferred germline counterpart to investigate the roles of SHMs in conferring IOMA's neutralization potency and breadth. Impacts on neutralization for each variant were evaluated, and this information was used to design minimally mutated IOMA-class variants (IOMAmin) that incorporated the fewest SHMs required for achieving IOMA's neutralization breadth. A cryoelectron microscopy (cryo-EM) structure of an IOMAmin variant bound to Env was used to further interpret characteristics of IOMA variants to elucidate how IOMA's structural features correlate with its neutralization mechanism, informing the design of IOMA-targeting immunogens.
靶向CD4结合位点(CD4bs)的HIV-1广泛中和抗体(bNAbs)具有一些罕见特征,这些特征对通过疫苗接种诱导产生这些bNAbs构成了挑战。IOMA类CD4bs bNAbs具有较少的罕见特征和体细胞超突变(SHMs)来实现广泛中和,因此为疫苗诱导的bNAb开发提供了一条潜在可行的途径。在此,我们构建了一个IOMA变体文库,其中每个SHM都单独回复到推断的种系对应物,以研究SHMs在赋予IOMA中和效力和广度方面的作用。评估了每个变体对中和的影响,并利用这些信息设计了最小突变的IOMA类变体(IOMAmin),其包含实现IOMA中和广度所需的最少SHMs。与Env结合的IOMAmin变体的冷冻电子显微镜(cryo-EM)结构被用于进一步解释IOMA变体的特征,以阐明IOMA的结构特征与其中和机制之间的关系,为靶向IOMA的免疫原设计提供信息。