Identification of autoantigens recognized by the 2F5 and 4E10 broadly neutralizing HIV-1 antibodies.
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Many human monoclonal antibodies that neutralize multiple clades of HIV-1 are polyreactive and bind avidly to mammalian autoantigens. Indeed, the generation of neutralizing antibodies to the 2F5 and 4E10 epitopes of HIV-1 gp41 in man may be proscribed by immune tolerance because mice expressing the V(H) and V(L) regions of 2F5 have a block in B cell development that is characteristic of central tolerance. This developmental blockade implies the presence of tolerizing autoantigens that are mimicked by the membrane-proximal external region of HIV-1 gp41. We identify human kynureninase (KYNU) and splicing factor 3b subunit 3 (SF3B3) as the primary conserved, vertebrate self-antigens recognized by the 2F5 and 4E10 antibodies, respectively. 2F5 binds the H4 domain of KYNU which contains the complete 2F5 linear epitope (ELDKWA). 4E10 recognizes an epitope of SF3B3 that is strongly dependent on hydrophobic interactions. Opossums carry a rare KYNU H4 domain that abolishes 2F5 binding, but they retain the SF3B3 4E10 epitope. Immunization of opossums with HIV-1 gp140 induced extraordinary titers of serum antibody to the 2F5 ELDKWA epitope but little or nothing to the 4E10 determinant. Identification of structural motifs shared by vertebrates and HIV-1 provides direct evidence that immunological tolerance can impair humoral responses to HIV-1.
SubjectAmino Acid Sequence
HIV Envelope Protein gp41
Hydrophobic and Hydrophilic Interactions
RNA Splicing Factors
env Gene Products, Human Immunodeficiency Virus
Published Version (Please cite this version)10.1084/jem.20121977
Publication InfoAlam, S Munir; Cain, DW; Haynes, Barton Ford; Holl, TM; Kelsoe, Garnett; Kepler, TB; ... Yang, G (2013). Identification of autoantigens recognized by the 2F5 and 4E10 broadly neutralizing HIV-1 antibodies. J Exp Med, 210(2). pp. 241-256. 10.1084/jem.20121977. Retrieved from http://hdl.handle.net/10161/10900.
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Professor in Medicine
Research Interests. Biophysical analysis of coreceptor modulation of TCR-MHC interactions. One of our research interests is to study the molecular mechanisms of T cell recognition. We have particular interest in understanding the trimolecular interactions between membrane bound T cell receptor (TCR-CD3 complex) and its ligand, the peptide-MHC complex (pMHC), and co-receptor molecules. We are using different biophysical approaches which include surface plasmon resonance, isothermal titr
Frederic M. Hanes Professor of Medicine
The Haynes lab is studying host innate and adaptive immune responses to the human immunodeficiency virus (HIV), tuberculosis (TB), and influenza in order to find the enabling technology to make preventive vaccines against these three major infectious diseases. Mucosal Immune Responses in Acute HIV Infection The Haynes lab is working to determine why broadly neutralizing antibodies are rarely made in acute HIV infection (AHI), currently a major obstacle in the de
James B. Duke Professor of Immunology
1. Lymphocyte development and antigen-driven diversification of immunoglobulin and T cell antigen receptor genes. 2. The germinal center reaction and mechanisms for clonal selection and self - tolerance. The origins of autoimmunity. 3. Interaction of innate- and adaptive immunity and the role of inflammation in lymphoid organogenesis. 4. The role of secondary V(D)J gene rearrangment in lymphocyte development and malignancies. 5. Mathematical modeling of immune responses,
Adjunct Professor in the Department of Medicine
Dr. Liao is a Professor of Medicine and Research Director of Duke Human Vaccine Institute. Dr. Liao is a MD virologistt rained in China. In early 1980’s, Dr. Liao made major contributions to the first isolation of epidemic hemorrhagic fever virus (hataanvirus) from Apodemus agraius using tissue culture in China. The successful identification and isolation of Hataanvirus enabled the early diagnosis and treatment of the disease, and advancement of HFRS research towards prevention by de
University Distinguished Service Professor of Radiology
The focus of this laboratory is the study of structure/function relationships in biological macromolecules and their binding interactions. The principal method we use for system characterization is magnetic resonance spectroscopy. One specific area of interest is the structural characterization of functional domains in proteins which regulate the transcription of DNA coding for biosynthetic enzymes. The system under current investigation is the methionine repressor protein metJ, its cor
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