title: IGHV1-69 B cell chronic lymphocytic leukemia antibodies cross-react with HIV-1 and hepatitis C virus antigens as well as intestinal commensal bacteria.
abstract: 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.
authors.affiliation: Duke Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Kwan-Ki
authors.initials: KK
authors.lastname: Hwang
authors.affiliation: Duke Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Ashley M
authors.initials: AM
authors.lastname: Trama
authors.affiliation: Duke Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Kozink
authors.affiliation: Duke Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: Duke Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Kevin
authors.initials: K
authors.lastname: Wiehe
authors.affiliation: Duke Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Abby J
authors.initials: AJ
authors.lastname: Cooper
authors.affiliation: Duke Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Shi-Mao
authors.initials: SM
authors.lastname: Xia
authors.affiliation: Duke Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Minyue
authors.initials: M
authors.lastname: Wang
authors.affiliation: Duke Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Dawn J
authors.initials: DJ
authors.lastname: Marshall
authors.affiliation: Duke Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: John
authors.initials: J
authors.lastname: Whitesides
authors.affiliation: Duke Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Munir
authors.initials: M
authors.lastname: Alam
authors.affiliation: Duke Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Georgia D
authors.initials: GD
authors.lastname: Tomaras
authors.affiliation: The Karches Center for Chronic Lymphocytic Leukemia Research, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Allen
authors.affiliation: The Karches Center for Chronic Lymphocytic Leukemia Research, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
authors.forename: Kanti R
authors.initials: KR
authors.lastname: Rai
authors.affiliation: School of Immunity and Infection, Institute of Biomedical Research, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Jane
authors.initials: J
authors.lastname: McKeating
authors.affiliation: The Karches Center for Chronic Lymphocytic Leukemia Research, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
authors.forename: Rosa
authors.initials: R
authors.lastname: Catera
authors.affiliation: The Karches Center for Chronic Lymphocytic Leukemia Research, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
authors.forename: Xiao-Jie
authors.initials: XJ
authors.lastname: Yan
authors.affiliation: The Karches Center for Chronic Lymphocytic Leukemia Research, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
authors.forename: Charles C
authors.initials: CC
authors.lastname: Chu
authors.affiliation: Department of Immunology, Duke University School of Medicine, Durham, North Carolina, United States of America.
authors.forename: Garnett
authors.initials: G
authors.lastname: Kelsoe
authors.affiliation: Duke Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Hua-Xin
authors.initials: HX
authors.lastname: Liao
authors.affiliation: The Karches Center for Chronic Lymphocytic Leukemia Research, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Chiorazzi
authors.affiliation: Duke Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Barton F
authors.initials: BF
authors.lastname: Haynes
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000276:immunology; D000912:Antibodies, Neoplasm / Q000276:immunology*; D001419:Bacteria / Q000276:immunology*; D045744:Cell Line, Tumor; D003429:Cross Reactions / Q000276:immunology*; D015488:HIV Antigens / Q000737:chemistry / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology; D015497:HIV-1 / Q000276:immunology; D016174:Hepacivirus / Q000276:immunology; D018936:Hepatitis C Antigens / Q000276:immunology*; D006801:Humans; D006825:Hybridomas / Q000276:immunology; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D007422:Intestines / Q000382:microbiology*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology*; D008969:Molecular Sequence Data; D010266:Paraproteins / Q000378:metabolism; D011485:Protein Binding; D011947:Receptors, Antigen, B-Cell / Q000276:immunology*; D011994:Recombinant Proteins / Q000378:metabolism; D016415:Sequence Alignment; D013559:Symbiosis; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D015488:HIV Antigens; D018936:Hepatitis C Antigens; C000598276:IGHV1-69 protein, human; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D010266:Paraproteins; D011947:Receptors, Antigen, B-Cell; D011994:Recombinant Proteins