Identification of autoantigens recognized by the 2F5 and 4E10 broadly neutralizing HIV-1 antibodies.
Abstract
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.
Type
Journal articleSubject
Amino Acid SequenceAnimals
Antibodies, Monoclonal
Antibodies, Neutralizing
Autoantigens
B-Lymphocytes
Cell Line
Conserved Sequence
Epitopes
HIV Antibodies
HIV Envelope Protein gp41
HIV-1
Humans
Hydrolases
Hydrophobic and Hydrophilic Interactions
Immune Tolerance
Immunization
Mice
Opossums
Phylogeny
RNA Splicing Factors
RNA-Binding Proteins
env Gene Products, Human Immunodeficiency Virus
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https://hdl.handle.net/10161/10900Published Version (Please cite this version)
10.1084/jem.20121977Publication Info
Yang, Guang; Holl, T Matt; Liu, Yang; Li, Yi; Lu, Xiaozhi; Nicely, Nathan I; ... Kelsoe,
Garnett (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 https://hdl.handle.net/10161/10900.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
S. Munir Alam
Professor in Medicine
Research Interests.
The Alam laboratory’s primary research is focused on understanding the biophysical
properties of antigen-antibody binding and the molecular events of early B cell activation
using the HIV-1 broadly neutralizing antibody (bnAb) lineage models. We are studying
how HIV-1 Envelope proteins of varying affinities are sensed by B cells expressing
HIV-1 bnAbs or their germline antigen receptors and initiate early signaling events
for their activation. In the lon
Derek Wilson Cain
Associate Professor in Medicine
My research focuses on the interactions of T cells and B cells during infection or
following vaccination. I am particularly interested in the inter- and intracellular
events that take place within germinal centers, the anatomic site of antibody evolution
during an immune response.
Barton Ford Haynes
Frederic M. Hanes Distinguished Professor of Medicine
Barton F. Haynes, M.D. is the Frederic M. Hanes Professor of Medicine and Immunology,
and Director of the Duke Human Vaccine Institute. Prior to leading the DHVI, Dr. Haynes
served as Chief of the Division of Rheumatology, Allergy and Clinical Immunology,
and later as Chair of the Department of Medicine. As Director of the Duke Human Vaccine
Institute, Bart Haynes is leading a team of investigators working on vaccines for
emerging infections, including tuberculosis, pandemic influenza, emergi
Garnett H. Kelsoe
James B. Duke Distinguished 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,
Hua-Xin Liao
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
This author no longer has a Scholars@Duke profile, so the information shown here reflects
their Duke status at the time this item was deposited.
Nathan I. Nicely
Assistant Professor in Medicine
Nathan Nicely, Ph.D., is an Assistant Professor of Medicine with the Duke Human Vaccine
Institute and Director of the Duke University X-ray Crystallography shared resource.
His major research interests lie in the structural biology of anti-HIV antibodies
and HIV virion coat proteins. Dr. Nicely received his Ph.D. in Structural and Molecular
Biochemistry from NC State University in 2005 with Dr. Carla Mattos. He then completed
a postdoctoral fellowship with Dr. Al Claiborne in the Center for S
Leonard D. Spicer
University Distinguished Service Professor Emeritus
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 corepressor
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