Neutralization Takes Precedence Over IgG or IgA Isotype-related Functions in Mucosal HIV-1 Antibody-mediated Protection.
Abstract
HIV-1 infection occurs primarily through mucosal transmission. Application of biologically
relevant mucosal models can advance understanding of the functional properties of
antibodies that mediate HIV protection, thereby guiding antibody-based vaccine development.
Here, we employed a human ex vivo vaginal HIV-1 infection model and a rhesus macaque
in vivo intrarectal SHIV challenge model to probe the protective capacity of monoclonal
broadly-neutralizing (bnAb) and non-neutralizing Abs (nnAbs) that were functionally
modified by isotype switching. For human vaginal explants, we developed a replication-competent,
secreted NanoLuc reporter virus system and showed that CD4 binding site bnAbs b12
IgG1 and CH31 IgG1 and IgA2 isoforms potently blocked HIV-1JR-CSF and HIV-1Bal26 infection.
However, IgG1 and IgA nnAbs, either alone or together, did not inhibit infection despite
the presence of FcR-expressing effector cells in the tissue. In macaques, the CH31
IgG1 and IgA2 isoforms infused before high-dose SHIV challenge were completely to
partially protective, respectively, while nnAbs (CH54 IgG1 and CH38 mIgA2) were non-protective.
Importantly, in both mucosal models IgG1 isotype bnAbs were more protective than the
IgA2 isotypes, attributable in part to greater neutralization activity of the IgG1
variants. These findings underscore the importance of potent bnAb induction as a primary
goal of HIV-1 vaccine development.
Type
Journal articleSubject
AntibodiesHIV-1
IgA
IgG
Mucosal immunology
Neutralizing antibodies
Non-human primate rectal challenge model
Vaginal explants
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https://hdl.handle.net/10161/13341Published Version (Please cite this version)
10.1016/j.ebiom.2016.11.024Publication Info
Astronomo, Rena D; Santra, Sampa; Ballweber-Fleming, Lamar; Westerberg, Katharine
G; Mach, Linh; Hensley-McBain, Tiffany; ... McElrath, Juliana M (n.d.). Neutralization Takes Precedence Over IgG or IgA Isotype-related Functions in Mucosal
HIV-1 Antibody-mediated Protection. EBioMedicine, 14. pp. 97-111. 10.1016/j.ebiom.2016.11.024. Retrieved from https://hdl.handle.net/10161/13341.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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Thomas Norton Denny
Professor in Medicine
Thomas N. Denny, MSc, M.Phil, is the Chief Operating Officer of the Duke Human Vaccine
Institute (DHVI) and the Center for HIV/AIDS Vaccine Immunology (CHAVI), and a Professor
of Medicine in the Department of Medicine at Duke University Medical Center. He is
also an Affiliate Member of the Duke Global Health Institute. He has recently been
appointed to the Duke University Fuqua School of Business Health Sector Advisory Council.
Previously, he was an Associate Professor of Pathology, Laboratory M
Guido Ferrari
Professor in Surgery
The activities of the Ferrari Laboratory are based on both independent basic research
and immune monitoring studies. The research revolves around three main areas of interest:
class I-mediated cytotoxic CD8+ T cell responses, antibody-dependent cellular cytotoxicity
(ADCC), gene expression in NK and T cellular subsets upon infection with HIV-1. With
continuous funding over the last 11 years from the NIH and Bill & Melinda Gates Foundation
along with many other productive collaborations wi
Barton Ford Haynes
Frederic M. Hanes Distinguished 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
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
David Charles Montefiori
Professor in Surgery
Dr. Montefiori is Professor and Director of the Laboratory for AIDS Vaccine Research
and Development in the Department of Surgery, Division of Surgical Sciences, Duke
University Medical Center. His major research interests are viral immunology and AIDS
vaccine development, with a special emphasis on neutralizing antibodies. One of his
highest priorities is to identify immunogens that generate broadly cross-reactive
neutralizing antibodies for inclusion in HIV vaccines. Many aspects of the
Justin Joseph Pollara
Associate Professor in Surgery
Georgia Doris Tomaras
Professor in Surgery
Dr. Georgia Tomaras is a tenured Professor of Surgery, Professor of Immunology, Professor
of Molecular Genetics and Microbiology and is a Fellow of the American Academy of
Microbiology (AAM) and a Fellow of the American Association for the Advancement of
Science (AAAS). Dr. Tomaras is Co-Director of the Center for Human Systems Immunology
(CHSI) Duke University and Director of the Duke Center for AIDS Research (CFAR). Her
national and international leadership roles i
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