IGHV1-69 B cell chronic lymphocytic leukemia antibodies cross-react with HIV-1 and hepatitis C virus antigens as well as intestinal commensal bacteria

Kwan-Ki Hwang, Ashley M Trama, Daniel M Kozink, Xi Chen, Kevin Wiehe, Abby J Cooper, Shi-Mao Xia, Minyue Wang, Dawn J Marshall, John Whitesides, Munir Alam, Georgia D Tomaras, Steven L Allen, Kanti R Rai, Jane McKeating, Rosa Catera, Xiao-Jie Yan, Charles C Chu, Garnett Kelsoe, Hua-Xin LiaoNicholas Chiorazzi, Barton F Haynes

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B-cell chronic lymphocytic leukemia (B-CLL) patients expressing unmutated immunoglobulin heavy variable regions (IGHVs) use the IGHV1-69 B cell receptor (BCR) in 25% of cases. Since HIV-1 envelope gp41 antibodies also frequently use IGHV1-69 gene segments, we hypothesized that IGHV1-69 B-CLL precursors may contribute to the gp41 B cell response during HIV-1 infection. To test this hypothesis, we rescued 5 IGHV1-69 unmutated antibodies as heterohybridoma IgM paraproteins and as recombinant IgG1 antibodies from B-CLL patients, determined their antigenic specificities and analyzed BCR sequences. IGHV1-69 B-CLL antibodies were enriched for reactivity with HIV-1 envelope gp41, influenza, hepatitis C virus E2 protein and intestinal commensal bacteria. These IGHV1-69 B-CLL antibodies preferentially used IGHD3 and IGHJ6 gene segments and had long heavy chain complementary determining region 3s (HCDR3s) (≥21 aa). IGHV1-69 B-CLL BCRs exhibited a phenylalanine at position 54 (F54) of the HCDR2 as do rare HIV-1 gp41 and influenza hemagglutinin stem neutralizing antibodies, while IGHV1-69 gp41 antibodies induced by HIV-1 infection predominantly used leucine (L54) allelic variants. These results demonstrate that the B-CLL cell population is an expansion of members of the innate polyreactive B cell repertoire with reactivity to a number of infectious agent antigens including intestinal commensal bacteria. The B-CLL IGHV1-69 B cell usage of F54 allelic variants strongly suggests that IGHV1-69 B-CLL gp41 antibodies derive from a restricted B cell pool that also produces rare HIV-1 gp41 and influenza hemagglutinin stem antibodies.

Original languageEnglish
Article numbere90725
Number of pages9
JournalPLoS ONE
Issue number3
Publication statusPublished - 10 Mar 2014


  • Alleles
  • Amino Acid Sequence
  • Antibodies, Monoclonal
  • Antibodies, Neoplasm
  • Bacteria
  • Cell Line, Tumor
  • Cross Reactions
  • HIV Antigens
  • HIV Infections
  • HIV-1
  • Hepacivirus
  • Hepatitis C Antigens
  • Humans
  • Hybridomas
  • Immunoglobulin Heavy Chains
  • Immunoglobulin Variable Region
  • Intestines
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Molecular Sequence Data
  • Paraproteins
  • Protein Binding
  • Receptors, Antigen, B-Cell
  • Recombinant Proteins
  • Sequence Alignment
  • Symbiosis
  • Treatment Outcome


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