scholarly journals Nonneutralizing antibodies binding to the surface glycoprotein of lymphocytic choriomeningitis virus reduce early virus spread

2006 ◽  
Vol 203 (8) ◽  
pp. 2033-2042 ◽  
Author(s):  
Lars Hangartner ◽  
Raphaël M. Zellweger ◽  
Mattia Giobbi ◽  
Jacqueline Weber ◽  
Bruno Eschli ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Cytotoxic T Lymphocyte ◽  
Antigenic Site ◽  
Neutralizing Antibody ◽  
Lymphocytic Choriomeningitis ◽  
Lymphocytic Choriomeningitis Virus ◽  
Antibody Binding ◽  
Surface Glycoprotein ◽  
Dependent Manner ◽  
Viral Spread

The biological relevance of nonneutralizing antibodies elicited early after infection with noncytopathic persistence-prone viruses is unclear. We demonstrate that cytotoxic T lymphocyte–deficient TgH(KL25) mice, which are transgenic for the heavy chain of the lymphocytic choriomeningitis virus (LCMV)–neutralizing monoclonal antibody KL25, mount a focused neutralizing antibody response following LCMV infection, and that this results in the emergence of neutralization escape virus variants. Further investigation revealed that some of the escape variants that arose early after infection could still bind to the selecting antibody. In contrast, no antibody binding could be detected for late isolates, indicating that binding, but nonneutralizing, antibodies exerted a selective pressure on the virus. Infection of naive TgH(KL25) mice with distinct escape viruses differing in their antibody-binding properties revealed that nonneutralizing antibodies accelerated clearance of antibody-binding virus variants in a partly complement-dependent manner. Virus variants that did not bind antibodies were not affected. We therefore conclude that nonneutralizing antibodies binding to the same antigenic site as neutralizing antibodies are biologically relevant by limiting early viral spread.

scholarly journals New Connections: Cell-to-Cell HIV-1 Transmission, Resistance to Broadly Neutralizing Antibodies, and an Envelope Sorting Motif

2017 ◽  
Vol 91 (9) ◽  
Author(s):  
S. Abigail Smith ◽  
Cynthia A. Derdeyn
Keyword(s):  
Neutralizing Antibodies ◽  
Differential Susceptibility ◽  
Neutralizing Antibody ◽  
Dependent Manner ◽  
Broadly Neutralizing Antibodies ◽  
Cell Infection ◽  
Viral Spread ◽  
Broadly Neutralizing Antibody ◽  
Hiv 1

ABSTRACT HIV-1 infection from cell-to-cell may provide an efficient mode of viral spread in vivo and could therefore present a significant challenge for preventative or therapeutic strategies based on broadly neutralizing antibodies. Indeed, Li et al. (H. Li, C. Zony, P. Chen, and B. K. Chen, J. Virol. 91:e02425-16, 2017, https://doi.org/10.1128/JVI.02425-16 ) showed that the potency and magnitude of multiple HIV-1 broadly neutralizing antibody classes are decreased during cell-to-cell infection in a context-dependent manner. A functional motif in gp41 appears to contribute to this differential susceptibility by modulating exposure of neutralization epitopes.

scholarly journals Enhanced Virus Clearance by Early Inducible Lymphocytic Choriomeningitis Virus-Neutralizing Antibodies in Immunoglobulin-Transgenic Mice

1998 ◽  
Vol 72 (3) ◽  
pp. 2253-2258 ◽  
Author(s):  
Peter Seiler ◽  
Ulrich Kalinke ◽  
Thomas Rülicke ◽  
Etienne M. Bucher ◽  
Christian Böse ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Antibody Response ◽  
Acute Phase ◽  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Lymphocytic Choriomeningitis ◽  
Lymphocytic Choriomeningitis Virus ◽  
Immunoglobulin M ◽  
Neutralizing Monoclonal Antibody ◽  
Lcmv Infection

ABSTRACT Following infection of mice with lymphocytic choriomeningitis virus (LCMV), virus-neutralizing antibodies appear late, after 30 to 60 days. Such neutralizing antibodies play an important role in protection against reinfection. To analyze whether a neutralizing antibody response which developed earlier could contribute to LCMV clearance during the acute phase of infection, we generated transgenic mice expressing LCMV-neutralizing antibodies. Transgenic mice expressing the immunoglobulin μ heavy chain of the LCMV-neutralizing monoclonal antibody KL25 (H25 transgenic mice) mounted LCMV-neutralizing immunoglobulin M (IgM) serum titers within 8 days after infection. This early inducible LCMV-neutralizing antibody response significantly improved the host’s capacity to clear the infection and did not cause an enhancement of disease after intracerebral (i.c.) LCMV infection. In contrast, mice which had been passively administered LCMV-neutralizing antibodies and transgenic mice exhibiting spontaneous LCMV-neutralizing IgM serum titers (HL25 transgenic mice expressing the immunoglobulin μ heavy and the κ light chain) showed an enhancement of disease after i.c. LCMV infection. Thus, early-inducible LCMV-neutralizing antibodies can contribute to viral clearance in the acute phase of the infection and do not cause antibody-dependent enhancement of disease.

scholarly journals Protection from cytomegalovirus viremia following glycoprotein B vaccination is not dependent on neutralizing antibodies

2018 ◽  
Vol 115 (24) ◽  
pp. 6273-6278 ◽  
Author(s):  
Ilona Baraniak ◽  
Barbara Kropff ◽  
Lyn Ambrose ◽  
Megan McIntosh ◽  
Gary R. McLean ◽  
...  
Keyword(s):  
Antibody Response ◽  
Neutralizing Antibodies ◽  
De Novo ◽  
Natural Infection ◽  
Neutralizing Antibody ◽  
Glycoprotein B ◽  
Solid Organ ◽  
Viral Glycoprotein ◽  
Viral Spread

Human cytomegalovirus (HCMV) is an important pathogen in transplant patients and in congenital infection. Previously, we demonstrated that vaccination with a recombinant viral glycoprotein B (gB)/MF59 adjuvant formulation before solid organ transplant reduced viral load parameters post transplant. Reduced posttransplant viremia was directly correlated with antibody titers against gB consistent with a humoral response against gB being important. Here we show that sera from the vaccinated seronegative patients displayed little evidence of a neutralizing antibody response against cell-free HCMV in vitro. Additionally, sera from seronegative vaccine recipients had minimal effect on the replication of a strain of HCMV engineered to be cell-associated in a viral spread assay. Furthermore, although natural infection can induce antibody-dependent cellular cytotoxicity (ADCC) responses, serological analysis of seronegative vaccinees again presented no evidence of a substantial ADCC-promoting antibody response being generated de novo. Finally, analyses for responses against major antigenic domains of gB following vaccination were variable, and their pattern was distinct compared with natural infection. Taken together, these data argue that the protective effect elicited by the gB vaccine is via a mechanism of action in seronegative vaccinees that cannot be explained by neutralization or the induction of ADCC. More generally, these data, which are derived from a human challenge model that demonstrated that the gB vaccine is protective, highlight the need for more sophisticated analyses of new HCMV vaccines over and above the quantification of an ability to induce potent neutralizing antibody responses in vitro.

A Randomized Dose-Escalating Phase I Trial of a Replication-Deficient Lymphocytic Choriomeningitis Virus Vector-Based Vaccine Against Human Cytomegalovirus

2020 ◽  
Author(s):  
Michael Schwendinger ◽  
Georges Thiry ◽  
Beatrice De Vos ◽  
Geert Leroux-Roels ◽  
Jacques Bruhwyler ◽  
...  
Keyword(s):  
Phase I ◽  
Human Cytomegalovirus ◽  
Neutralizing Antibodies ◽  
Phase I Trial ◽  
Lymphocytic Choriomeningitis ◽  
Lymphocytic Choriomeningitis Virus ◽  
High Dose ◽  
Double Blind ◽  
High Fraction ◽  
Dose Dependent

Abstract Background A vaccine (HB-101) consisting of 2 nonreplicating lymphocytic choriomeningitis virus (LCMV) vectors expressing the human cytomegalovirus antigens glycoprotein B (gB) and the 65-kD phosphoprotein (pp65), respectively, is in development to prevent cytomegalovirus infection. Methods HB-101 was tested in cytomegalovirus-naive, healthy adults in a randomized, double-blind, placebo-controlled, dose-escalation Phase I trial. Fifty-four subjects received low, medium, or high dose of HB-101 or placebo by intramuscular administration at Month 0, 1, and 3. Safety and immunogenicity were the respective primary and secondary endpoints. Subjects were followed for 12 months after the initial immunization. Results Vaccination was associated with transient mild to moderate adverse events. HB-101 administration induced dose-dependent gB- and pp65-specific cellular responses, dominated by pp65-specific CD8 T cells, a high fraction of which were polyfunctional. Two administrations were sufficient to elicit dose-dependent gB-binding and cytomegalovirus-neutralizing antibodies (Abs). Cytomegalovirus-specific immune responses were boosted after each administration. Only 1 of 42 vaccine recipients mounted a transient LCMV vector-neutralizing Ab response. Conclusions HB-101 was well tolerated and induced cytomegalovirus-specific polyfunctional CD8 T-cell and neutralizing Ab responses in the majority of subjects. Lack of vector-neutralizing Ab responses should facilitate booster vaccinations. These results justify further clinical evaluation of this vaccine candidate.

scholarly journals The infectivity of progeny adenovirus in the presence of neutralizing antibody

2021 ◽  
Vol 102 (4) ◽  
Author(s):  
Takamasa Hirai ◽  
Anna Sato ◽  
Naoya Koizumi ◽  
Yoh Kurioka ◽  
Yui Suzuki ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Magnetic Beads ◽  
Secondary Infection ◽  
Neutralizing Antibody ◽  
Dependent Manner ◽  
Gastrointestinal Infections ◽  
Serotype 5 ◽  
Sorting System ◽  
Fiber Proteins ◽  
Adenovirus Receptor

Human adenoviruses (Ads), common pathogens that cause upper respiratory and gastrointestinal infections, are blocked by neutralizing antibodies (nAbs). However, Ads are not fully eliminated even in hosts with nAbs. In this study, we assessed the infectivity of progeny Ad serotype 5 (Ad5) in the presence of nAb. The infectivity of Ad5 was evaluated according to the expression of the Ad genome and reporter gene. Infection by wild-type Ad5 and Ad5 vector continued to increase until 3 days after infection even in the presence of nAb. We established an assay for determining the infection levels of progeny Ad5 using a sorting system with magnetic beads and observed little difference in progeny Ad5 counts in the presence and absence of nAb 1 day after infection. Moreover, progeny Ad5 in the presence of nAb more effectively infected coxsackievirus and adenovirus receptor (CAR)-positive cells than CAR-negative cells. We investigated the function of fiber proteins, which are the binding partners of CAR, during secondary infection, observing that fibre proteins spread from infected cells to adjacent cells in a CAR-dependent manner. In conclusion, this study revealed that progeny Ad5 could infect cells even in the presence of nAb, differing from the common features of the Ad5 infection cycle. Our findings may be useful for developing new therapeutic agents against Ad infection.

scholarly journals Immunodominant B cell epitope in SARS-CoV-2 RBD comprises a B.1.351 and P.1 mutation hotspot: implications for viral spread and antibody escape

2021 ◽  
Author(s):  
Keity Souza Santos ◽  
Jamille Ramos Oliveira ◽  
Rafael Rahal G. Machado ◽  
Helen Andrade Arcuri ◽  
Jhosiene Yukari Magawa ◽  
...  
Keyword(s):  
B Cell ◽  
Neutralizing Antibodies ◽  
Immune Escape ◽  
Cell Epitope ◽  
Antibody Binding ◽  
Published Data ◽  
Immunodominant Epitope ◽  
Marked Rise ◽  
Viral Spread ◽  
Iga Antibody

AbstractRecent SARS-CoV-2 variants pose important concerns due to their higher transmissibility (1) and escape (2) from previous infections or vaccine-induced neutralizing antibodies (nAb). The receptor binding domain (RBD) of the Spike protein is a major nAb target (3), but data on its B cell epitopes are still lacking. Using a peptide microarray, we identified an immunodominant epitope (S415-429) recognized by 68% of sera from 71 convalescent Brazilians infected with the ancestral variant. In contrast with previous studies, we have identified a linear IgG and IgA antibody binding epitope within the RBD. IgG and IgA antibody levels for this epitope positively correlated with nAb titers, suggesting a potential target of antibody neutralizing activity. Interestingly, this immunodominant RBD region harbors the mutation hotspot site K417 present in P.1 (K417T) and B.1.351 (K417N) variants. In silico simulation analyses indicate impaired RBD binding to nAb in both variants and that a glycosylation in the B.1.351 417N could further hinder antibody binding as compared to the K417T mutation in P.1. This is in line with published data showing that nAb from either convalescents or anti-CoV-2 vaccinees are less effective towards B.1.351 than for P.1. Our data support the occurrence of immune pressure and selection involving this immunodominant epitope that may have critically contributed to the recent COVID-19 marked rise in Brazil and South Africa, and pinpoint a potential additional immune escape mechanism for SARS-CoV-2.

scholarly journals Engineered receptor binding domain immunogens elicit pan-coronavirus neutralizing antibodies

2020 ◽  
Author(s):  
Blake M. Hauser ◽  
Maya Sangesland ◽  
Evan C. Lam ◽  
Jared Feldman ◽  
Ashraf S. Yousif ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Binding Domain ◽  
Surface Glycoprotein ◽  
Binding Motif ◽  
Receptor Binding Domain ◽  
Broadly Neutralizing Antibodies ◽  
Major Surface Glycoprotein ◽  
Major Surface

AbstractEffective countermeasures are needed against emerging coronaviruses of pandemic potential, similar to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Designing immunogens that elicit broadly neutralizing antibodies to conserved viral epitopes on the major surface glycoprotein, spike, such as the receptor binding domain (RBD) is one potential approach. Here, we report the generation of homotrimeric RBD immunogens from different sarbecoviruses using a stabilized, immune-silent trimerization tag. We find that that a cocktail of homotrimeric sarbecovirus RBDs can elicit a neutralizing response to all components even in context of prior SARS-CoV-2 imprinting. Importantly, the cross-neutralizing antibody responses are focused towards conserved RBD epitopes outside of the ACE-2 receptor-binding motif. This may be an effective strategy for eliciting broadly neutralizing responses leading to a pan-sarbecovirus vaccine.

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