Polymorphisms in human immunoglobulin heavy chain genes can influence the function of SARS-CoV-2 neutralizing antibodies ImmunityCP karolinskainst polymorphism gene genetics SARSCoV2 coronavirus covid antibody antibodies
By Pooja Toshniwal PahariaDec 14 2022Reviewed by Danielle Ellis, B.Sc. In a recent study published in Immunity, researchers isolated SARS-CoV-2 spike protein-targeted mAbs from convalescent healthcare workers , emphasizing the IGHV1-69 gene, the gene with the greatest structural and allelic variation.
An individual with numerous anti-S memory B lymphocytes and elevated IGHV composition was chosen, from whom 29 anti-SARS-CoV-2 mAbs were isolated. The effects of IGHV use were evaluated by reverting a robust IGHV1-69*20 utilizing neutralizing Ab, CAB-I47, to sequences of the IGHV1-69*20 allele and five other alleles of IGHV1-69. High-resolution cryo-electron microscopy was performed to assess molecular Ab-SARS-CoV-2 S receptor-binding domain interactions.
Further, PMBC ribonucleic acid sequencing was performed, and Ab VJ sites from the sorted cells were amplified by RT-PCR. IGHV1-69 allele sequence alignment was assessed, and CAB-147 mAb was chosen to assess the role of IGHV1-69 allele variations. Results CAB-I47 Ab depended critically on allele use, and SARS-CoV-2 neutralization was maintained when reverting the variable site to the IGHV1-69*20 allele but lost when reverting to other IGHV1-69 alleles. Structural analysis findings showed that the F55 and R50 germline-encoded genetic polymorphisms in IGHV1-69 were essential for high-binding affinity S RBD-Ab interactions.
The average SHMs for neutralizing mAbs were 10% and 6.0%, and 10% in the amino acid sequence and the nucleotide sequence, respectively, and the J gene lacked SHMs. SP14 elicited IGHV1-69 using potent neutralizing mAbs. The ancestral SARS-CoV-2 strain neutralization potential of CAB-I47gL*20 was 6.0-fold lower than other Abs.
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