tetano
Editor, Senior Moderator
Cell Rep
. 2024 May 27;43(6):114265.
doi: 10.1016/j.celrep.2024.114265. Online ahead of print. An unconventional VH1-2 antibody tolerates escape mutations and shows an antigenic hotspot on SARS-CoV-2 spike
Banghui Liu[SUP] 1 [/SUP], Xuefeng Niu[SUP] 2 [/SUP], Yijun Deng[SUP] 3 [/SUP], Zhaoyong Zhang[SUP] 3 [/SUP], Yanqun Wang[SUP] 3 [/SUP], Xijie Gao[SUP] 4 [/SUP], Huan Liang[SUP] 3 [/SUP], Zimu Li[SUP] 1 [/SUP], Qian Wang[SUP] 5 [/SUP], Yuanyi Cheng[SUP] 3 [/SUP], Qiuluan Chen[SUP] 6 [/SUP], Shuangshuang Huang[SUP] 3 [/SUP], Yingxian Pan[SUP] 3 [/SUP], Mengzhen Su[SUP] 7 [/SUP], Xiancheng Lin[SUP] 3 [/SUP], Chuanying Niu[SUP] 7 [/SUP], Yinglin Chen[SUP] 3 [/SUP], Wenyi Yang[SUP] 3 [/SUP], Yudi Zhang[SUP] 8 [/SUP], Qihong Yan[SUP] 3 [/SUP], Jun He[SUP] 1 [/SUP], Jincun Zhao[SUP] 9 [/SUP], Ling Chen[SUP] 10 [/SUP], Xiaoli Xiong[SUP] 11 [/SUP]
Affiliations
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein continues to evolve antigenically, impacting antibody immunity. D1F6, an affinity-matured non-stereotypic VH1-2 antibody isolated from a patient infected with the SARS-CoV-2 ancestral strain, effectively neutralizes most Omicron variants tested, including XBB.1.5. We identify that D1F6 in the immunoglobulin G (IgG) form is able to overcome the effect of most Omicron mutations through its avidity-enhanced multivalent S-trimer binding. Cryo-electron microscopy (cryo-EM) and biochemical analyses show that three simultaneous epitope mutations are generally needed to substantially disrupt the multivalent S-trimer binding by D1F6 IgG. Antigenic mutations at spike positions 346, 444, and 445, which appeared in the latest variants, have little effect on D1F6 binding individually. However, these mutations are able to act synergistically with earlier Omicron mutations to impair neutralization by affecting the interaction between D1F6 IgG and the S-trimer. These results provide insight into the mechanism by which accumulated antigenic mutations facilitate evasion of affinity-matured antibodies.
Keywords: CP: Immunology; CP: Microbiology; SARS-CoV-2; affinity maturation; escape mutation; mouse model; neutralizing antibody.
. 2024 May 27;43(6):114265.
doi: 10.1016/j.celrep.2024.114265. Online ahead of print. An unconventional VH1-2 antibody tolerates escape mutations and shows an antigenic hotspot on SARS-CoV-2 spike
Banghui Liu[SUP] 1 [/SUP], Xuefeng Niu[SUP] 2 [/SUP], Yijun Deng[SUP] 3 [/SUP], Zhaoyong Zhang[SUP] 3 [/SUP], Yanqun Wang[SUP] 3 [/SUP], Xijie Gao[SUP] 4 [/SUP], Huan Liang[SUP] 3 [/SUP], Zimu Li[SUP] 1 [/SUP], Qian Wang[SUP] 5 [/SUP], Yuanyi Cheng[SUP] 3 [/SUP], Qiuluan Chen[SUP] 6 [/SUP], Shuangshuang Huang[SUP] 3 [/SUP], Yingxian Pan[SUP] 3 [/SUP], Mengzhen Su[SUP] 7 [/SUP], Xiancheng Lin[SUP] 3 [/SUP], Chuanying Niu[SUP] 7 [/SUP], Yinglin Chen[SUP] 3 [/SUP], Wenyi Yang[SUP] 3 [/SUP], Yudi Zhang[SUP] 8 [/SUP], Qihong Yan[SUP] 3 [/SUP], Jun He[SUP] 1 [/SUP], Jincun Zhao[SUP] 9 [/SUP], Ling Chen[SUP] 10 [/SUP], Xiaoli Xiong[SUP] 11 [/SUP]
Affiliations
- PMID: 38805396
- DOI: 10.1016/j.celrep.2024.114265
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein continues to evolve antigenically, impacting antibody immunity. D1F6, an affinity-matured non-stereotypic VH1-2 antibody isolated from a patient infected with the SARS-CoV-2 ancestral strain, effectively neutralizes most Omicron variants tested, including XBB.1.5. We identify that D1F6 in the immunoglobulin G (IgG) form is able to overcome the effect of most Omicron mutations through its avidity-enhanced multivalent S-trimer binding. Cryo-electron microscopy (cryo-EM) and biochemical analyses show that three simultaneous epitope mutations are generally needed to substantially disrupt the multivalent S-trimer binding by D1F6 IgG. Antigenic mutations at spike positions 346, 444, and 445, which appeared in the latest variants, have little effect on D1F6 binding individually. However, these mutations are able to act synergistically with earlier Omicron mutations to impair neutralization by affecting the interaction between D1F6 IgG and the S-trimer. These results provide insight into the mechanism by which accumulated antigenic mutations facilitate evasion of affinity-matured antibodies.
Keywords: CP: Immunology; CP: Microbiology; SARS-CoV-2; affinity maturation; escape mutation; mouse model; neutralizing antibody.