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

V_H replacement occurs through RAG-mediated secondary recombination to change unwanted IgH genes and diversify antibody repertoire. The biological significance of V_H replacement remains to be explored. Here, we show that V_H 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 V_H replacement products encoding anti-HIV antibodies are highly mutated; the V_H 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 V_H replacement. Taken together, these findings uncovered a potentially significant contribution of V_H replacement products to the generation of anti-HIV antibodies.