scholarly journals Neutralizing Monoclonal Antibodies Reduce Human Cytomegalovirus Infection and Spread in Developing Placentas

Vaccines ◽  
2019 ◽  
Vol 7 (4) ◽  
pp. 135 ◽  
Author(s):  
Takako Tabata ◽  
Matthew Petitt ◽  
June Fang-Hoover ◽  
Daniel C. Freed ◽  
Fengsheng Li ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Human Cytomegalovirus ◽  
Virus Transmission ◽  
Passive Immunization ◽  
First Trimester ◽  
Clinical Strain ◽  
Stromal Fibroblasts ◽  
Virion Assembly ◽  
Effective Strategies ◽  
Hyperimmune Globulin

Congenital human cytomegalovirus (HCMV) infection is a leading cause of birth defects worldwide, yet the most effective strategies for preventing virus transmission during pregnancy are unknown. We measured the efficacy of human monoclonal antibodies (mAbs) to HCMV attachment/entry factors glycoprotein B (gB) and the pentameric complex, gH/gL-pUL128–131, in preventing infection and spread of a clinical strain in primary placental cells and explants of developing anchoring villi. A total of 109 explants from five first-trimester placentas were cultured, and infection was analyzed in over 400 cell columns containing ~120,000 cytotrophoblasts (CTBs). mAbs to gB and gH/gL, 3-25 and 3-16, respectively, neutralized infection in stromal fibroblasts and trophoblast progenitor cells. mAbs to pUL128-131 of the pentameric complex, 1-103 and 2-18, neutralized infection of amniotic epithelial cells better than mAbs 3-25 and 3-16 and hyperimmune globulin. Select mAbs neutralized infection of cell column CTBs, with mAb 2-18 most effective, followed by mAb 3-25. Treatment of anchoring villi with mAbs postinfection reduced spread in CTBs and impaired formation of virion assembly compartments, with mAb 2-18 achieving better suppression at lower concentrations. These results predict that antibodies generated by HCMV vaccines or used for passive immunization have the potential to reduce transplacental transmission and congenital disease.

scholarly journals A High-Affinity Native Human Antibody Neutralizes Human Cytomegalovirus Infection of Diverse Cell Types

2014 ◽  
Vol 59 (3) ◽  
pp. 1558-1568 ◽  
Author(s):  
Lawrence M. Kauvar ◽  
Keyi Liu ◽  
Minha Park ◽  
Neal DeChene ◽  
Robert Stephenson ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Human Cytomegalovirus ◽  
Hcmv Infection ◽  
Ex Vivo ◽  
Virus Transmission ◽  
Passive Immunization ◽  
Cell Types ◽  
Human Antibody ◽  
Viral Glycoprotein ◽  
High Affinity

ABSTRACTHuman cytomegalovirus (HCMV) is the most common infection causing poor outcomes among transplant recipients. Maternal infection and transplacental transmission are major causes of permanent birth defects. Although no active vaccines to prevent HCMV infection have been approved, passive immunization with HCMV-specific immunoglobulin has shown promise in the treatment of both transplant and congenital indications. Antibodies targeting the viral glycoprotein B (gB) surface protein are known to neutralize HCMV infectivity, with high-affinity binding being a desirable trait, both to compete with low-affinity antibodies that promote the transmission of virus across the placenta and to displace nonneutralizing antibodies binding nearby epitopes. Using a miniaturized screening technology to characterize secreted IgG from single human B lymphocytes, 30 antibodies directed against gB were previously cloned. The most potent clone, TRL345, is described here. Its measured affinity was 1 pM for the highly conserved site I of the AD-2 epitope of gB. Strain-independent neutralization was confirmed for 15 primary HCMV clinical isolates. TRL345 prevented HCMV infection of placental fibroblasts, smooth muscle cells, endothelial cells, and epithelial cells, and it inhibited postinfection HCMV spread in epithelial cells. The potential utility for preventing congenital transmission is supported by the blockage of HCMV infection of placental cell types central to virus transmission to the fetus, including differentiating cytotrophoblasts, trophoblast progenitor cells, and placental fibroblasts. Further, TRL345 was effective at controlling anex vivoinfection of human placental anchoring villi. TRL345 has been utilized on a commercial scale and is a candidate for clinical evaluation.

Increase in Reported Prevalence of Microcephaly in Infants Born to Women Living in Areas with Confirmed Zika Virus Transmission During the First Trimester of Pregnancy — Brazil, 2015

2016 ◽  
Vol 65 (9) ◽  
Author(s):  
Wanderson Kleber de Oliveira ◽  
Juan Cortez-Escalante ◽  
Wanessa Tenório Gonçalves Holanda De Oliveira ◽  
Greice Madeleine Ikeda do Carmo ◽  
Cláudio Maierovitch Pessanha Henriques ◽  
...  
Keyword(s):  
Zika Virus ◽  
Virus Transmission ◽  
First Trimester ◽  
First Trimester Of Pregnancy

Increase in Reported Prevalence of Microcephaly in Infants Born to Women Living in Areas with Confirmed Zika Virus Transmission During the First Trimester of Pregnancy — Brazil, 2015

2016 ◽  
Vol 65 (9) ◽  
pp. 242-247 ◽  
Author(s):  
Wanderson Kleber de Oliveira ◽  
Juan Cortez-Escalante ◽  
Wanessa Tenório Gonçalves Holanda De Oliveira ◽  
Greice Madeleine Ikeda do Carmo ◽  
Cláudio Maierovitch Pessanha Henriques ◽  
...  
Keyword(s):  
Zika Virus ◽  
Virus Transmission ◽  
First Trimester ◽  
First Trimester Of Pregnancy

scholarly journals Maternal exposure to a high-magnitude earthquake during pregnancy influences pre-reading skills in early childhood

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Luis Federico Bátiz ◽  
Yasna K. Palmeiro-Silva ◽  
Gregory E. Rice ◽  
Lara J. Monteiro ◽  
Albert M. Galaburda ◽  
...  
Keyword(s):  
Reading Skills ◽  
First Trimester ◽  
Maternal Exposure ◽  
Stressful Events ◽  
Stressful Event ◽  
Prenatally Exposed ◽  
Alphabet Knowledge ◽  
Print Knowledge ◽  
Effective Strategies ◽  
High Magnitude

AbstractExposure to an adverse prenatal environment can influence fetal development and result in long-lasting changes in the offspring. However, the association between maternal exposure to stressful events during pregnancy and the achievement of pre-reading skills in the offspring is unknown. Here we examined the association between prenatal exposure to the Chilean high-magnitude earthquake that occurred on February 27th, 2010 and the development of early reading precursors skills (listening comprehension, print knowledge, alphabet knowledge, vocabulary, and phonological awareness) in children at kindergarten age. This multilevel retrospective cohort study including 3280 children, of whom 2415 were unexposed and 865 were prenatally exposed to the earthquake shows substantial evidence that maternal exposure to an unambiguously stressful event resulted in impaired pre-reading skills and that a higher detrimental effect was observed in those children who had been exposed to the earthquake during the first trimester of gestation. In addition, females were more significantly affected by the exposure to the earthquake than their male peers in alphabet knowledge; contrarily, males were more affected than females in print knowledge skills. These findings suggest that early intervention programs for pregnant women and/or children exposed to prenatal stress may be effective strategies to overcome impaired pre-reading skills in children.

scholarly journals Neutralizing Mechanisms of Two Human Monoclonal Antibodies Against Human Cytomegalovirus Glycoprotein 130/55

1992 ◽  
Vol 73 (10) ◽  
pp. 2705-2707 ◽  
Author(s):  
Y. Ohizumi ◽  
H. Suzuki ◽  
Y.-I. Matsumoto ◽  
Y. Masuho ◽  
Y. Numazaki
Keyword(s):  
Monoclonal Antibodies ◽  
Human Cytomegalovirus ◽  
Human Monoclonal Antibodies

scholarly journals Characterization and protective activity of monoclonal antibodies directed against Fe (3+) ABC transporter substrate-binding protein of Glaesserella parasuis

2021 ◽  
Vol 52 (1) ◽  
Author(s):  
Kexin Zhu ◽  
Dong Yu ◽  
Jiahui An ◽  
Yufeng Li
Keyword(s):  
Monoclonal Antibodies ◽  
Abc Transporter ◽  
Subunit Vaccine ◽  
Binding Protein ◽  
Substrate Binding ◽  
Passive Immunization ◽  
Enzyme Linked Immunosorbent Assay ◽  
Control Group ◽  
And Control ◽  
Substrate Binding Protein

AbstractGlässer’s disease is caused by the agent Glaesserella parasuis and is difficult to prevent and control. Candidate screening for subunit vaccines contributes to the prevention of this disease. Therefore, in this study, the inactivated G. parasuis reference serovar 5 strain (G. parasuis-5) was used to generate specific monoclonal antibodies (mAbs) to screen subunit vaccine candidates. Six mAbs (1A12, 3E3, 4C6, 2D1, 3E6, and 4B2) were screened, and they all reacted with the G. parasuis serovar 5 strain according to laser confocal microscopy and flow cytometry (FCM). Indirect enzyme-linked immunosorbent assay (ELISA) showed that one mAb 2D1, can react with all 15 reference serovars of G. parasuis. Protein mass spectrometry and Western blot analysis demonstrated that mAb 2D1 specifically reacts with Fe (3+) ABC transporter substrate-binding protein. A complement killing assay found that the colony numbers of bacteria were significantly reduced in the G. parasuis-5 group incubated with mAb 2D1 (p < 0.01) in comparison with the control group. Opsonophagocytic assays demonstrated that mAb 2D1 significantly enhanced the phagocytosis of 3D4/21 cells by G. parasuis (p < 0.05). RAW264.7 cells with stronger phagocytic ability were also used for the opsonophagocytic assay, and the difference was highly significant (p < 0.01). Passive immunization of mice revealed that mAb 2D1 can eliminate the bacteria in the blood and provide protection against G. parasuis-5. Our study found one mAb that can be used to prevent and control G. parasuis infection in vivo and in vitro, which may suggest that Fe (3+) ABC transporter substrate-binding protein is an immunodominant antigen and a promising candidate for subunit vaccine development.

scholarly journals Human Cytomegalovirus Drives WDR5 to the Virion Assembly Compartment to Facilitate Virion Assembly

2020 ◽  
Author(s):  
Bo Yang ◽  
YongXuan Yao ◽  
Hui Wu ◽  
Hong Yang ◽  
Xue-Hui Ma ◽  
...  
Keyword(s):  
Human Cytomegalovirus ◽  
Hcmv Infection ◽  
Antiviral Treatment ◽  
Critical Role ◽  
Virion Assembly ◽  
Potential Target ◽  
Nuclear Egress ◽  
Early Endosomes ◽  
Hcmv Replication ◽  
Assembly Compartment

AbstractWe previously reported that human cytomegalovirus (HCMV) utilizes the cellular protein WDR5 to facilitate capsid nuclear egress. Here, we further show that HCMV infection drives WDR5 to the perinuclear region by a mechanism that requires viral replication and intact microtubules. WDR5 accumulated in the virion assembly compartment (vAC) and co-localized with vAC markers of gamma-tubulin (γ-tubulin), early endosomes, and viral vAC marker proteins pp65, pp28, and glycoprotein B (gB). WDR5 interacted with multiple virion proteins, including MCP, pp150, pp65, pIRS1, and pTRS1, which may explain the increasing WDR5 accumulation in the vAC during infection. WDR5 was then incorporated into HCMV virions and localized to the tegument layer, as demonstrated by fractionation and immune-gold electron microscopy. Thus, WDR5 is driven to the vAC and incorporated into virions, suggesting that WDR5 facilitates HCMV replication at later stage of virion assembly besides the capsid nuclear egress stage. These data highlight that WDR5 is a potential target for antiviral therapy.ImportanceHuman cytomegalovirus (HCMV) has a large (~235-kb) genome that contains over 170 ORFs and exploits numerous cellular factors to facilitate its replication. In the late phase of HCMV infection cytoplasmic membranes are profoundly reconfigured to establish the virion assembly compartment (vAC), which is important for efficient assembly of progeny virions. We previously reported that WDR5 promotes HCMV nuclear egress. Here, we show that WDR5 is further driven to the vAC and incorporated into virions, perhaps to facilitate efficient virion maturation. This work identified potential roles for WDR5 in HCMV replication in the cytoplasmic stages of virion assembly. Taken together, WDR5 plays a critical role in HCMV capsid nuclear egress and is important for virion assembly, and thus is a potential target for antiviral treatment of HCMV-associated diseases.

scholarly journals Specificity and effector functions of non-neutralizing gB-specific monoclonal antibodies isolated from healthy individuals with human cytomegalovirus infection

2020 ◽  
Author(s):  
Matthew L. Goodwin ◽  
Helen S. Webster ◽  
Hsuan-Yuan Wang ◽  
Jennifer A. Jenks ◽  
Cody S. Nelson ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Human Cytomegalovirus ◽  
Effector Cell ◽  
Natural Infection ◽  
Congenital Infection ◽  
Neutralizing Antibody ◽  
Antibody Responses ◽  
Domain Specificity ◽  
Cell Functions ◽  
The Impact

AbstractHuman cytomegalovirus (HCMV) is the most common congenital infection, and the leading nongenetic cause of sensorineural hearing loss (SNHL) in newborns globally. A gB subunit vaccine administered with adjuvent MF59 (gB/MF59) is the most efficacious tested to-date, achieving 50% efficacy in preventing infection of HCMV-seronegative mothers. We recently discovered that gB/MF59 vaccination elicited primarily non-neutralizing antibody responses, that HCMV strains acquired by vaccinees more often included strains with gB genotypes that are distinct from the vaccine antigen, and that protection against HCMV acquisition correlated with ability of vaccine-elicited antibodies to bind to membrane associated gB. Thus, we hypothesized that gB-specific non-neutralizing antibody binding breadth and function are dependent on their epitope and genotype specificity as well as their ability to interact with membrane-associated gB. Twenty-four gB-specific monoclonal antibodies (mAbs) isolated from naturally HCMV-infected individuals were mapped for gB domain specificity by binding antibody multiplex assay (BAMA) and for genotype preference binding to membrane-associated gB presented on transfected cells. We defined their non-neutralizing functions including antibody dependent cellular phagocytosis (ADCP) and antibody dependent cellular cytotoxicity (ADCC). The isolated gB-specific non-neutralizing mAbs were primarily specific for Domain II and linear antigenic domain 2 site 2 (AD2). We observed variability in mAb gB genotype binding preference, with increased binding to gB genotypes 2 and 4. Functional studies identified two gB-specific mAbs that facilitate ADCP and have binding specificities of AD2 and Domain II. This investigation provides novel understanding on the impact of gB domain specificity and antigenic variability on gB-specific non-neutralizing antibody responses.ImportanceHCMV is the most common congenital infection worldwide, but development of a successful vaccine remains elusive. gB-specific non-neutralizing mAbs, represent a distinct anti-HCMV Ab subset implicated in the protection against primary infection during numerous phase-II gB/MF59 vaccine trials. By studying non-neutralizing gB-specific mAbs from naturally infected individuals, this study provides novel characterization of binding site specificity, genotypic preference, and effector cell functions mediated by mAbs elicited in natural infection. We found that a panel of twenty-four gB-specific non-neutralizing mAbs bind across multiple regions of the gB protein, traditionally through to be targeted by neutralizing mAbs only, and bind differently to gB depending if the protein is soluble versus embedded in a membrane. This investigation provides novel insight into the gB-specific binding characteristics and effector cell functions mediated by non-neutralizing gB-specific mAbs elicited through natural infection, providing new endpoints for future vaccine development.

Production of Monoclonal Antibodies Against Phosphoprotein 65 from Human Cytomegalovirus

Hybridoma ◽  
2007 ◽  
Vol 26 (3) ◽  
pp. 173-177 ◽  
Author(s):  
Li-Jun Xu ◽  
Hang-Ping Yao ◽  
Jun Fan ◽  
Dan Li ◽  
Nan-Ping Wu
Keyword(s):  
Monoclonal Antibodies ◽  
Human Cytomegalovirus
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