title: Contribution of V(H) replacement products to the generation of anti-HIV antibodies.
abstract: 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.
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Liao
authors.forename: Jun-tao
authors.initials: JT
authors.lastname: Guo
authors.forename: Miles D
authors.initials: MD
authors.lastname: Lange
authors.forename: Run
authors.initials: R
authors.lastname: Fan
authors.forename: Michael
authors.initials: M
authors.lastname: Zemlin
authors.forename: Kaihong
authors.initials: K
authors.lastname: Su
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Guan
authors.forename: Zhixin
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D000595:Amino Acid Sequence; D000916:Antibody Diversity / Q000235:genetics / Q000276:immunology*; D015704:CD4 Antigens / Q000737:chemistry / Q000276:immunology; D022801:Complementarity Determining Regions / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D015483:HIV Antibodies / Q000737:chemistry / Q000276:immunology*; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000276:immunology; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D007135:Immunoglobulin Variable Region / Q000235:genetics / Q000276:immunology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary
chemical_list: D015704:CD4 Antigens; D022801:Complementarity Determining Regions; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region