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research-article
Author(s):
Marcy R. Auerbach 1 ,
Donghong Yan 2 ,
Rajesh Vij 3 ,
Jo-Anne Hongo 3 ,
Gerald Nakamura 3 ,
Jean-Michel Vernes 4 ,
Y. Gloria Meng 4 ,
Samantha Lein 3 ,
Pamela Chan 4 ,
Jed Ross 5 ,
Richard Carano 5 ,
Rong Deng 6 ,
Nicholas Lewin-Koh 7 ,
Min Xu 2 ,
Becket Feierbach 1 , *
Publication date (Electronic): 10 April 2014
Journal: PLoS Pathogens
Publisher: Public Library of Science
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Human cytomegalovirus (HCMV) is the most common cause of congenital virus infection. Congenital HCMV infection occurs in 0.2–1% of all births, and causes birth defects and developmental abnormalities, including sensorineural hearing loss and developmental delay. Several key studies have established the guinea pig as a tractable model for the study of congenital HCMV infection and have shown that polyclonal antibodies can be protective [1]– [3]. In this study, we demonstrate that an anti-guinea pig CMV (GPCMV) glycoprotein H/glycoprotein L neutralizing monoclonal antibody protects against fetal infection and loss in the guinea pig. Furthermore, we have delineated the kinetics of GPCMV congenital infection, from maternal infection (salivary glands, seroconversion, placenta) to fetal infection (fetus and amniotic fluid). Our studies support the hypothesis that a neutralizing monoclonal antibody targeting an envelope GPCMV glycoprotein can protect the fetus from infection and may shed light on the therapeutic intervention of HCMV congenital infection in humans. Human cytomegalovirus (HCMV) is the most common cause of congenital virus infection and causes developmental abnormalities, including hearing loss and developmental delay. Although there is no therapy for congenital HCMV disease, there is evidence from both human and animal studies that antibodies can have efficacy in this setting. Such studies have focused exclusively on polyclonal antibodies, in which the targets of protective antibodies are unknown. Guinea pigs have been used as a model of human maternal fetal transmission of infection because of similarities in placental anatomy between human and guinea pig. Furthermore, guinea pig CMV (GPCMV) has been demonstrated to cross the placenta and cause fetal infection and loss, similar to the effects of infection with HCMV. However, the kinetics of maternal and fetal infection in this model has not been carefully investigated. In this work, we have delineated the kinetics of maternal to fetal infection and found that congenital infection is rapid following maternal infection. Importantly, we demonstrate that a monoclonal antibody against a protein critical for viral entry protects pregnant guinea pigs against fetal infection. Thus, our studies may be informative for development of a therapeutic intervention to treat congenital HCMV infection in humans. Abstract
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Most cited references35
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Correction of multi-gene deficiency in vivo using a single 'self-cleaving' 2A peptide-based retroviral vector.
Andrea L Szymczak, Creg J Workman, Yao Wang … (2004)
Attempts to generate reliable and versatile vectors for gene therapy and biomedical research that express multiple genes have met with limited success. Here we used Picornavirus 'self-cleaving' 2A peptides, or 2A-like sequences from other viruses, to generate multicistronic retroviral vectors with efficient translation of four cistrons. Using the T-cell receptor:CD3 complex as a test system, we show that a single 2A peptide-linked retroviral vector can be used to generate all four CD3 proteins (CD3epsilon, gamma, delta, zeta), and restore T-cell development and function in CD3-deficient mice. We also show complete 2A peptide-mediated 'cleavage' and stoichiometric production of two fluorescent proteins using a fluorescence resonance energy transfer-based system in multiple cell types including blood, thymus, spleen, bone marrow and early stem cell progenitors.
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Passive immunization during pregnancy for congenital cytomegalovirus infection.
Aaron A. Best, , Stuart Adler … (2005)
Currently, there is no effective intervention for a primary cytomegalovirus (CMV) infection during pregnancy. We studied pregnant women with a primary CMV infection. The therapy group comprised women whose amniotic fluid contained either CMV or CMV DNA and who were offered intravenous CMV hyperimmune globulin at a dose of 200 U per kilogram of maternal weight. A prevention group, consisting of women with a recent primary infection before 21 weeks' gestation or who declined amniocentesis, was offered monthly hyperimmune globulin (100 U per kilogram intravenously). In the therapy group, 31 women received hyperimmune globulin, only 1 (3 percent) of whom gave birth to an infant with CMV disease (symptomatic at birth and handicapped at two or more years of age), as compared with 7 of 14 women who did not receive hyperimmune globulin (50 percent). Thus, hyperimmune globulin therapy was associated with a significantly lower risk of congenital CMV disease (adjusted odds ratio, 0.02; 95 percent confidence interval, -infinity to 0.15; P<0.001). In the prevention group, 37 women received hyperimmune globulin, 6 (16 percent) of whom had infants with congenital CMV infection, as compared with 19 of 47 women (40 percent) who did not receive hyperimmune globulin. Thus, hyperimmune globulin therapy was associated with a significantly lower risk of congenital CMV infection (adjusted odds ratio, 0.32; 95 percent confidence interval, 0.10 to 0.94; P=0.04). Hyperimmune globulin therapy significantly (P<0.001) increased CMV-specific IgG concentrations and avidity and decreased natural killer cells and HLA-DR+ cells and had no adverse effects. Treatment of pregnant women with CMV-specific hyperimmune globulin is safe, and the findings of this nonrandomized study suggest that it may be effective in the treatment and prevention of congenital CMV infection. A controlled trial of this agent may now be appropriate. Copyright 2005 Massachusetts Medical Society.
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Isolation of human monoclonal antibodies that potently neutralize human cytomegalovirus infection by targeting different epitopes on the gH/gL/UL128-131A complex.
Annalisa Macagno, E Dander, Federica Sallusto … (2009)
Human cytomegalovirus (HCMV) is a widely circulating pathogen that causes severe disease in immunocompromised patients and infected fetuses. By immortalizing memory B cells from HCMV-immune donors, we isolated a panel of human monoclonal antibodies that neutralized at extremely low concentrations (90% inhibitory concentration [IC(90)] values ranging from 5 to 200 pM) HCMV infection of endothelial, epithelial, and myeloid cells. With the single exception of an antibody that bound to a conserved epitope in the UL128 gene product, all other antibodies bound to conformational epitopes that required expression of two or more proteins of the gH/gL/UL128-131A complex. Antibodies against gB, gH, or gM/gN were also isolated and, albeit less potent, were able to neutralize infection of both endothelial-epithelial cells and fibroblasts. This study describes unusually potent neutralizing antibodies against HCMV that might be used for passive immunotherapy and identifies, through the use of such antibodies, novel antigenic targets in HCMV for the design of immunogens capable of eliciting previously unknown neutralizing antibody responses.
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Author and article information
Contributors
Peter A. Barry: Role: Editor
Journal
Journal ID (nlm-ta): PLoS Pathog
Journal ID (iso-abbrev): PLoS Pathog
Journal ID (publisher-id): plos
Journal ID (pmc): plospath
Title: PLoS Pathogens
Publisher: Public Library of Science (San Francisco, USA )
ISSN (Print): 1553-7366
ISSN (Electronic): 1553-7374
Publication date Collection: April 2014
Publication date (Electronic): 10 April 2014
Volume: 10
Issue: 4
Electronic Location Identifier: e1004060
Affiliations
[1 ]Department of Infectious Diseases, Genentech, South San Francisco, California, United States of America
[2 ]Department of Translational Immunology, Genentech, South San Francisco, California, United States of America
[3 ]Department of Antibody Engineering, Genentech, South San Francisco, California, United States of America
[4 ]Department of Biochemical and Cellular Pharmacology, Genentech, South San Francisco, California, United States of America
[5 ]Department of Biomedical Imaging, Genentech, South San Francisco, California, United States of America
[6 ]Department of Clinical Pharmacology, Genentech, South San Francisco, California, United States of America
Author notes
* E-mail: becketf@ 123456gene.com
Article
Publisher ID: PPATHOGENS-D-13-02152
DOI: 10.1371/journal.ppat.1004060
PMC ID: 3983071
PubMed ID: 24722349
SO-VID: b3a5387c-0071-4b8b-86f6-fda5f04bd2ed
Copyright statement: Copyright @ 2014
License:
This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
History
Date received : 9 August 2013
Date accepted : 25 February 2014
Page count
Pages: 12
Funding
This research was funded by Genentech, Inc./Hoffmann La-Roche. The funders had no role in study design, data collection and analysis, decision to publish or any preparation of the manuscript.
Categories
Subject: Research Article
Subject: Biology and Life Sciences
Subject: Microbiology
Subject: Medicine and Health Sciences
Subject: Infectious Diseases
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