Contribution of VH replacement products to the generation of anti-HIV antibodies

• Published in: Clinical immunology (Orlando, Fla.) Vol. 146; no. 1; pp. 46 - 55
• Main Authors: Liao, Hongyan, Guo, Jun-tao, Lange, Miles D, Fan, Run, Zemlin, Michael, Su, Kaihong, Guan, Yongjun, Zhang, Zhixin
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.01.2013
• Subjects: Allergy and Immunology; Anti-HIV antibody; CD4i antibody; gp120; IgH gene; VH replacement; recombination signal sequence; complementarity determine region; cRSS; immunoglobulin; recombination activating gene products; CD4 binding induced; CD4i; IgH; IgH gene; CD4i antibody; CDR; immunoglobulin heavy chain; RSS; Anti-HIV antibody; HIV; human immunodeficiency virus; RAG; gp120; cryptic recombination signal sequence; V H replacement; Ig; VH replacement
• ISSN: 1521-6616; 1521-7035
• DOI: 10.1016/j.clim.2012.11.003

Abstract VH replacement occurs through RAG-mediated secondary recombination to change unwanted IgH genes and diversify antibody repertoire. The biological significance of VH replacement remains to be explored. Here, we show that VH replacement products are highly enriched in IgH genes encoding anti-HIV antibodies, including anti-gp41, anti-V3 loop, anti-gp120, CD4i, and PGT antibodies. In particular, 73% of the CD4i antibodies and 100% of the PGT antibodies are encoded by potential VH replacement products. Such frequencies are significantly higher than those in IgH genes derived from HIV infected individuals or autoimmune patients. The identified VH replacement products encoding anti-HIV antibodies are highly mutated; the VH replacement “footprints” within CD4i antibodies preferentially encode negatively charged amino acids within the IgH CDR3; many IgH encoding PGT antibodies are likely generated from multiple rounds of VH replacement. Taken together, these findings uncovered a potentially significant contribution of VH replacement products to the generation of anti-HIV antibodies.