Immune checkpoint modulation enhances HIV-1 antibody induction.
Abstract
Eliciting protective titers of HIV-1 broadly neutralizing antibodies (bnAbs) is a
goal of HIV-1 vaccine development, but current vaccine strategies have yet to induce
bnAbs in humans. Many bnAbs isolated from HIV-1-infected individuals are encoded by
immunoglobulin gene rearrangments with infrequent naive B cell precursors and with
unusual genetic features that may be subject to host regulatory control. Here, we
administer antibodies targeting immune cell regulatory receptors CTLA-4, PD-1 or OX40
along with HIV envelope (Env) vaccines to rhesus macaques and bnAb immunoglobulin
knock-in (KI) mice expressing diverse precursors of CD4 binding site HIV-1 bnAbs.
CTLA-4 blockade augments HIV-1 Env antibody responses in macaques, and in a bnAb-precursor
mouse model, CTLA-4 blocking or OX40 agonist antibodies increase germinal center B
and T follicular helper cells and plasma neutralizing antibodies. Thus, modulation
of CTLA-4 or OX40 immune checkpoints during vaccination can promote germinal center
activity and enhance HIV-1 Env antibody responses.
Type
Journal articleSubject
B-LymphocytesT-Lymphocytes, Helper-Inducer
Animals
Mice, Transgenic
Macaca mulatta
Humans
Mice
HIV-1
HIV Infections
AIDS Vaccines
Immunologic Factors
Antibodies, Blocking
HIV Antibodies
Vaccination
Lymphocyte Activation
Receptors, OX40
env Gene Products, Human Immunodeficiency Virus
Antibodies, Neutralizing
CTLA-4 Antigen
Transcriptome
CD4 Antigens
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https://hdl.handle.net/10161/21940Published Version (Please cite this version)
10.1038/s41467-020-14670-wPublication Info
(2020). Immune checkpoint modulation enhances HIV-1 antibody induction. Nature communications, 11(1). pp. 948. 10.1038/s41467-020-14670-w. Retrieved from https://hdl.handle.net/10161/21940.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
Mattia Bonsignori
Associate Professor in Medicine
HIV vaccine development Study of B-cell immune responses in HIV positive individuals
Determination of correlates of protective immunity to HIV Induction of broadly neutralizing
antibodies to HIV Development of multiplex functional assays for the evaluation at
a single-cell level of B-cell responses to vaccinations, infections and in vitro stimulation
Epidemiology and characterization of bacterial resistance determinants (past) </do
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.
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,
David Charles Montefiori
Professor in Surgery
Dr. Montefiori is Professor and Director of the Laboratory for HIV and COVID-19 Vaccine
Research & Development in the Department of Surgery, Division of Surgical Sciences
at Duke University Medical Center. His major research interests are viral immunology
and HIV and COVID-19 vaccine development, with a special emphasis on neutralizing
antibodies. Multiple aspects of HIV-1 neutralizing antibodies are studied in his laboratory,
including mechanisms of neutralization and escape,
Kevin O'Neil Saunders
Associate Professor in Surgery
Dr. Kevin O. Saunders graduated from Davidson College in 2005 with a bachelor of science
in biology. At Davidson College, he trained in the laboratory of Dr. Karen Hales identifying
the genetic basis of infertility. Dr. Saunders completed his doctoral research on
CD8+ T cell immunity against HIV-1 infection with Dr. Georgia Tomaras at Duke University
in 2010. He subsequently trained as a postdoctoral fellow in the laboratories of Drs.
Gary Nabel and John Mascola at the National Institutes of
Laurent Karl Verkoczy
Adjunct Professor in the Department of Medicine
Laurent Verkoczy, PhD is Associate Professor of Medicine and Pathology at Duke University
Medical Center. Dr.Verkoczy directs the Laboratory of B-cell Immunoregulation at the
Duke Human Vaccine Institute and also serves as a B-cell Focus Investigator in Duke’s
Center for HIV/AIDS Vaccine Immunology & Immunogen Discovery (CHAVI-ID) consortium.
He obtained his Ph.D. in Immunology from the University of Toronto in 2000 and completed
post-doctoral studies at The S
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.
Kevin J Wiehe
Norman L. Letvin Associate Professor in Medicine
Dr. Kevin Wiehe is the associate director of research, director of computational biology
and co-director of the Quantitative Research Division at the Duke Human Vaccine Institute
(DHVI). He has over 20 years of experience in the field of computational biology and
has expertise in computational structural biology, computational genomics, and computational
immunology.
For the past decade, he has applied his unique background to developing computational
approaches for studying the B cell
Chen-Hao Yeh
Assistant Professor in Medicine
Dr. Yeh completed his undergraduate and Master of Science degree at the National Taiwan
University in Taipei. He then pursued his Ph.D. at the University of Tokyo in Japan.
He moved to Durham in 2015 for postdoctoral training in Dr. Garnett Kelsoe’s laboratory
at the Duke Department of Immunology.
Dr. Yeh holds a broad academic background in biochemistry and immunology, with specific
training and expertise in lymphocyte development and differentiation. His research
has focused o
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