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Written by | Tour Bright
EBV (Epstein-Barr Virus) belongs to the γ-herpes virus, which is caused by infectious mononucleosis and a variety of B-cell lymphomas Major pathogens (eg, Burkitt and Hodgkin lymphoma) and epithelial cell carcinoma (eg, nasopharyngeal carcinoma, gastric cancer).
EBV is almost ubiquitous in adults, and may cause lymphoma
in immunocompromised organ and bone marrow transplant patients or other primary immunodeficient patients.
In addition, EBV can also cause multiple sclerosis
.
However, no preventive or therapeutic vaccine against EBV has been approved for marketing
to date.
Although intravenous immunoglobulin has been used in immunocompromised patients, breakthrough infections of EBV and HCMV (human cytomegalovirus) still occur
。 Immunocompromised patients are unable to develop an adequate immune response to prophylactic vaccines, so passive immunoprophylaxis with monoclonal antibodies may be indispensable for
blocking EBV infection.
EBV infection requires the fusion of viral membranes with host cell membranes and endosomal membranes, and a group of viral glycoproteins, including gH/gL or gH/gL/gp42
, is composed of the EBV membrane fusion machine.
The gH/gL of EBV can bind to adrenergic receptor A2 (EphA2) and integrins on the surface of epithelial cells, while gp42 of EBV can bind to MHC-II
, the major histocompatibility complex on the surface of B cells 。 In the past, there have been some monoclonal antibodies that interact with gH/gL or gH/gL/gp42 to neutralize and block EBV-infected epithelial cells and B cells, such as the monoclonal antibodies CL40, CL59 and E1D1 identified by the Jardetzky TS laboratory at Stanford University School of Medicine, and the monoclonal antibody AMMO1 identified by the McGuire AT laboratory at the University of Washington.
Monoclonal antibody 1D8 identified by Zhang Linqi's laboratory of Tsinghua University and Zeng Musheng Laboratory of Sun Yat-sen University Cancer Center for Cancer Prevention and Treatment
.
However, how does monoclonal antibody targeting EBV gH/gL play a role in neutralizing EBV infection and blocking EBV and cell fusion? What epitope segments on EBV gH/gL are easily neutralized and blocked by antibodies?
Recently, Professor Cohen JI and Joyce of the National Institute of Allergy and Infectious Diseases (NIAID) at IH Prof.
MG collaborated to publish an article in the journal Immunity Epstein-Barr virus gH/gL has multiple sites of vulnerability for virus neutralization and fusion inhibition Using a variety of serology, biochemistry, structural biology methods and humanized mouse challenge models, the epitope structure information on EBV gH/gL that is easily neutralized and inhibited by fusion was systematically revealed, which laid a theoretical foundation
for understanding EBV invasion and infection of cells and developing preventive or therapeutic vaccines.
First, the authors obtained peripheral blood from two patients recovering from EBV infection from Warren Magnuson Clinical Center in the United States, which had high neutralizing titers
for EBV-infected B cells and epithelial cells 。 The authors used fluorescently labeled gH/gL probes to isolate B cells that specifically recognize EBV gH/gL from peripheral blood, amplified the sequence of the measured immunoglobulin, and expressed six monoclonal antibodies (769A7, 769B10, 769C2, 769C5, 770F7, and 770F8) that can specifically bind gH/gL and gH/gL/gp42
。
Next, the authors used GFP-expressing EBV viruses to verify whether these monoclonal antibodies could neutralize EBV infection of epithelial cells and B cells, and found that monoclonal antibodies 769B10, 769C2, and 769A7 had the strongest ability to neutralize EBV infection B cells, while monoclonal antibodies 769B10, E1D1, 770F7, and 769C5 had the strongest ability to infect EBV in epithelial cells
。 And because gH/gL and gB are core fusion protein machines for EBV fusion with cell membranes, the authors used a luciferase-based cell-cell fusion assay The ability of these six monoclonal antibodies to inhibit viral fusion was evaluated, and it was found that 769C2, 769B10 and 769C5 had the strongest ability to block the fusion of EBV with B cells, while 769B10, 769C5 and 770F7 had the strongest ability to block the fusion of EBV with epithelial cells
.
Whether it is neutralizing or blocking fusion, monoclonal antibody 760B10 ranks first
.
Subsequently, the authors determined the binding and dissociation ability of monoclonal antibody to gH/gL or gH/gL/gp42 through biolayer interferometry, and found that the Fab of 769B10 and 770F7 had the strongest overall binding to gH/gL and gH/gL/gp42, and the KD values were less than 1nM.
However, the binding capacity of 769B10 to gH/gL/gp42 (K D=0.
46 nM) was significantly lower than that of gH/gL (KD=0.
03 nM).
Finally, the authors did an antibody competition assay The epitopes of different monoclonal antibodies bound to gH/gL were reasonably inferred, and it was found that 769B10 competed with CL40, 769C2 and 770F8, while monoclonal antibodies 769A7, 769C5 and 770F7 did not compete with other monoclonal antibodies.
This means that 769B10 with high neutralizing and high fusion blocking capacity can be combined with 6 other monoclonal antibodies, and the new monoclonal antibodies 769A7, 769C5, and 770F7 may recognize some new epitopes
.
In order to specifically analyze the structural information of different epitopes bound to monoclonal antibodies to EBV gH/gL/gp42, the authors packaged and analyzed the X-ray crystal structure and electron density maps
of monoclonal antibody 769B10, 769C2 and 769F7 bound to EBV gH/gL/gp42 polypeptides, respectively.
In terms of crystal structure, the total buried surface area (BSA) of 769B10 bound to gH/gL/gp42 is 1074 Å2, which is an antigen supersite (antigenic supersite), which can identify both gH and gL
.
From the electron density map of negative dyeing electron microscopy, the position of 769B10 binding gH/gL/gp42 has a coincident region with monoclonal antibody CL40 and AMMO1, and the binding region of 769B10 and AMMO1 is close to the KGD integrin-binding motif on gH/gL, which can significantly hinder the connection
between gH/gL and integrin.
Monoclonal antibody 769C2 can bind the N-terminal and gL of gH at the same time, and the overall embedded surface area BSA is 941Å 2; The pattern of monoclonal antibody 769F8 binding gH/gL to 769C2 is similar and explainsThis is the reason for the competitive relationship between the
two.
In 2020, Yan Jinghua, a researcher at the Institute of Microbiology of the Chinese Academy of Sciences, analyzed the crystal structure of the ligand-recognition domain of EBV gH/gL and its receptor EphA2.
In this paper, by comparing the regions where EphA2, monoclonal antibody 769C2 and monoclonal antibody E1D1 bind to EBV gH/gL, it is found that the regions where monoclonal antibody 769C2 and monoclonal antibody E1D1 bind to gH/gL and the region where EphA2 and gH/gL are bound by Yan Jinghua's laboratory have a large proportion of overlap, and the overall embedded surface area coincidence region is greater than 500 Å2, but the binding regions of monoclonal antibody 769C2 and monoclonal antibody E1D1 are close but not overlapping.
There is no competition between the two
.
The large overlap between 769C2 and the region of receptor EphA2-binding gH/gL found a structural basis for 769C2 blocking EBV infection in epithelial cells, while the neutralization or blocking effect of 769C2 on EBV-infected B cells may be affected by the binding angle, steric hindrance or other mechanisms of the monoclonal antibody
.
The monoclonal antibody 770F7 binds to both EBV gH and gL, and the overall embedded surface area BSA is 1050Å 2
.
770F7 recognizes a new epitope of gH/gL, located at the C terminal of gH; The recognition of monoclonal antibody CL59 with gH/gL is also located at the C terminal of gH, but opposite the 770F7 recognition region
.
The 4th domain D-IV at the c-terminal of gH is critical for the fusion of EBV with cells, so monoclonal antibody 770F7 can play the role of
fusion inhibition.
Summarizing the crystal structure of monoclonal antibody and EBV gH/gL previously analyzed and newly analyzed in this paper, the authors further analyze the vulnerable sites
on gH/gL that are easily neutralized or easily blocked by fusion 。 According to the order of gH from N terminal to C terminus, gH/gL can be divided into 4 domains of D-I, D-II, D-III, and d-IV, and different antibodies can recognize 7 different antigen regions on gH/gL: 2 of them are located in D-I, that is, 769C2-770F8 antigen site and E1D1 antigen site; 2 are located in DI-II, respectively AMMO1, 769B10 and CL40 identified sites and 769A7 identified sites; In the DII-III domain, it contains 1 antigen site bound by 769C5 and 1D8; In the DIII-IV domain, CL59 and 770F7 recognize two antigenic loci located on opposite sides
.
These epitopes occupy 40% of the surface of gH/gL, while the region above the 770F7 epitope near the gp42 spherical domain, the region between CL59 epitope and 769C2 epitope has not yet identified antibodies that play a neutralizing or fusion blocking effect
.
Analyzing the structure of binding of other herpesvirus neutralizing antibodies to their gH/gL proteins, the authors found that the monoclonal antibodies VZV RC and VZV94 of varicella zoster virus VZV bind to VZV gH/gL in a location similar to the region where 769B10 or CL40 binds to EBV gH/gL.
The binding region of monoclonal antibody 13H11 to HCMV gH/gL of human cytomegalovirus HCMV is similar to the region of CL40 binding to EBV gH/gL, the region where 3G16 binds to HCMV gH/gL is similar to the region where CL59 binds to EBV gH/gL, and the location of monoclonal antibody 1-32 binding to HCMV gH/gL is similar to the binding region
of 769C2 to EBV gH/gL 。 However, EBV monoclonal antibodies are only specific for EBV gH/gL, and VZV and HCMV monoclonal antibodies cannot bind to EBV gH/gL; The position of neutralizing antibody binding corresponding to gH/gL is conserved, but the protein sequence of different viruses gH/gL is different.
The use of monoclonal antibodies to bind to the gH/gL region can provide a reference
for the development of different herpesvirus vaccines or therapeutic antibodies.
At the end of the full paper, the authors transferred human CD34+ hematopoietic stem cells to irradiated NOG mice to develop human lymphocytes, and conducted humanized mouse challenge and challenge protection tests
by intravenous infusion of monoclonal antibody and EBV 。 By evaluating the alleviation of mouse weight loss, the increase of mouse survival rate, the decrease of blood and tissue virus content, the decrease of lymphoma occurrence, and whether visible skin lesions occur, the protective effect
of monoclonal antibody on EBV infection was discussed.
The experiments found that the monoclonal antibodies 769C2 and 769B10 had a long half-life in mice, 769B10 and 770F7 treated mice significantly reduced EBV virus titers in tissues, and 769B10-treated mice had the lowest EBV virus titers in their blood and effectively eliminated the occurrence
of lymphoma in vaccinated mice.
The full text starts from the isolation and identification of blood monoclonal antibodies from healthy donors, the detection of monoclonal antibodies to EBV gH/gL neutralization and fusion inhibition, the structural basis of monoclonal antibodies to neutralize and fusion inhibition, the epitope characteristics of EBV gH/gL that are easily neutralized and easily inhibited by fusion, and the comparison of different herpesvirus gH/gL neutralization and fusion inhibitory sites by antibodies.
From the perspective of the protective power of monoclonal antibody in the EBV challenge test of humanized mice, the epitopes that are easily targeted and neutralized and inhibited by fusion when EBV invades infected cells with the help of gH/gL are comprehensively and systematically studied, which lays a solid foundation for the further development and application of preventive and therapeutic EBV vaccines or antibodies, and also sets a benchmark and paradigm for the development of structure-based vaccines and antibodies against other pathogens
.
The corresponding author of the article is Cohen from the NIH's National Institute of Allergy and Infectious Diseases (NIAID).
Professor JI and Professor
Joyce MG.
Professor Cohen JI is the head of the Department of Medical Virology at NIAID, with a research interest in the pathogenesis of human herpesvirus, as well as the development of vaccines and monoclonal antibodies against human
herpesvirus.
Another corresponding author, Professor Joyce MG, is also the director of the U.
S.
Army Research Institute of Wald Reed and the Henry Jackson Foundation for the Advancement of Military Medicine Laboratory of Emerging Infectious Diseases; He is a structural biologist whose research interests lie in the use of X-ray crystallography and electron microscopy to resolve the structure of viral antigen-antibody interactions, and the structural design of vaccines and small molecule inhibitors
.
In 2019, Cohen JI cloned the expression of monoclonal antibody 769B10 from donor blood with high neutralizing EBV antibody titers, and this time he used a similar method to identify a group of 6 monoclonal antibodies including 769B10, and together with Joyce MG, he used structural biology to elucidate the epitope characteristics
of EBV gH/gL protein that are easily neutralized and easily inhibited by fusion.
Original link: https://doi.
org/10.
1016/j.
immuni.
2022.
10.
003
Platemaker: Eleven
1.
Chen WH, et al.
Epstein-Barr virus gH/gL has multiple sites of vulnerability for virus neutralization and fusion inhibition.
Immunity 2022.
2.
Bu W, et al.
Immunization with components of the fusion apparatus elicits antibodies that neutralize Epstein-Barr virus in B cells and epithelial cells.
Immunity 2019.
3.
Sathiyamoorthy K, et al.
Structural basis for Epstein-Barr virus host cell tropism mediated by pg42 and gHgL entry glycoproteins.
Nature Communication 2016.
4.
Sathiyamoorthy K, et al.
Inhibition of EBV-mediated membrane fusion by anti-gHgL antibodies.
PNAS 2017.
5.
Snijder J, et al.
An antibody targeting the fusion machinery neutralizes dual-tropic infection and defines a site of vulnerability on Epstein-Barr virus.
Immunity 2018.
6.
Su C, et al.
Molecular basis of EphA2 recognition by gHgL from gamma-herpesviruses.
Nature Communication 2020.
7.
Zhu QY, et al.
A potent and protective human neutralizing antibody targeting a novel vulnerable site of Epstein-Barr virus.
Nature Communication 2021.
EBV (Epstein-Barr Virus) belongs to the γ-herpes virus, which is caused by infectious mononucleosis and a variety of B-cell lymphomas Major pathogens (eg, Burkitt and Hodgkin lymphoma) and epithelial cell carcinoma (eg, nasopharyngeal carcinoma, gastric cancer).
EBV is almost ubiquitous in adults, and may cause lymphoma
in immunocompromised organ and bone marrow transplant patients or other primary immunodeficient patients.
In addition, EBV can also cause multiple sclerosis
.
However, no preventive or therapeutic vaccine against EBV has been approved for marketing
to date.
Although intravenous immunoglobulin has been used in immunocompromised patients, breakthrough infections of EBV and HCMV (human cytomegalovirus) still occur
。 Immunocompromised patients are unable to develop an adequate immune response to prophylactic vaccines, so passive immunoprophylaxis with monoclonal antibodies may be indispensable for
blocking EBV infection.
EBV infection requires the fusion of viral membranes with host cell membranes and endosomal membranes, and a group of viral glycoproteins, including gH/gL or gH/gL/gp42
, is composed of the EBV membrane fusion machine.
The gH/gL of EBV can bind to adrenergic receptor A2 (EphA2) and integrins on the surface of epithelial cells, while gp42 of EBV can bind to MHC-II
, the major histocompatibility complex on the surface of B cells 。 In the past, there have been some monoclonal antibodies that interact with gH/gL or gH/gL/gp42 to neutralize and block EBV-infected epithelial cells and B cells, such as the monoclonal antibodies CL40, CL59 and E1D1 identified by the Jardetzky TS laboratory at Stanford University School of Medicine, and the monoclonal antibody AMMO1 identified by the McGuire AT laboratory at the University of Washington.
Monoclonal antibody 1D8 identified by Zhang Linqi's laboratory of Tsinghua University and Zeng Musheng Laboratory of Sun Yat-sen University Cancer Center for Cancer Prevention and Treatment
.
However, how does monoclonal antibody targeting EBV gH/gL play a role in neutralizing EBV infection and blocking EBV and cell fusion? What epitope segments on EBV gH/gL are easily neutralized and blocked by antibodies?
Recently, Professor Cohen JI and Joyce of the National Institute of Allergy and Infectious Diseases (NIAID) at IH Prof.
MG collaborated to publish an article in the journal Immunity Epstein-Barr virus gH/gL has multiple sites of vulnerability for virus neutralization and fusion inhibition Using a variety of serology, biochemistry, structural biology methods and humanized mouse challenge models, the epitope structure information on EBV gH/gL that is easily neutralized and inhibited by fusion was systematically revealed, which laid a theoretical foundation
for understanding EBV invasion and infection of cells and developing preventive or therapeutic vaccines.
First, the authors obtained peripheral blood from two patients recovering from EBV infection from Warren Magnuson Clinical Center in the United States, which had high neutralizing titers
for EBV-infected B cells and epithelial cells 。 The authors used fluorescently labeled gH/gL probes to isolate B cells that specifically recognize EBV gH/gL from peripheral blood, amplified the sequence of the measured immunoglobulin, and expressed six monoclonal antibodies (769A7, 769B10, 769C2, 769C5, 770F7, and 770F8) that can specifically bind gH/gL and gH/gL/gp42
。
Next, the authors used GFP-expressing EBV viruses to verify whether these monoclonal antibodies could neutralize EBV infection of epithelial cells and B cells, and found that monoclonal antibodies 769B10, 769C2, and 769A7 had the strongest ability to neutralize EBV infection B cells, while monoclonal antibodies 769B10, E1D1, 770F7, and 769C5 had the strongest ability to infect EBV in epithelial cells
。 And because gH/gL and gB are core fusion protein machines for EBV fusion with cell membranes, the authors used a luciferase-based cell-cell fusion assay The ability of these six monoclonal antibodies to inhibit viral fusion was evaluated, and it was found that 769C2, 769B10 and 769C5 had the strongest ability to block the fusion of EBV with B cells, while 769B10, 769C5 and 770F7 had the strongest ability to block the fusion of EBV with epithelial cells
.
Whether it is neutralizing or blocking fusion, monoclonal antibody 760B10 ranks first
.
Subsequently, the authors determined the binding and dissociation ability of monoclonal antibody to gH/gL or gH/gL/gp42 through biolayer interferometry, and found that the Fab of 769B10 and 770F7 had the strongest overall binding to gH/gL and gH/gL/gp42, and the KD values were less than 1nM.
However, the binding capacity of 769B10 to gH/gL/gp42 (K D=0.
46 nM) was significantly lower than that of gH/gL (KD=0.
03 nM).
Finally, the authors did an antibody competition assay The epitopes of different monoclonal antibodies bound to gH/gL were reasonably inferred, and it was found that 769B10 competed with CL40, 769C2 and 770F8, while monoclonal antibodies 769A7, 769C5 and 770F7 did not compete with other monoclonal antibodies.
This means that 769B10 with high neutralizing and high fusion blocking capacity can be combined with 6 other monoclonal antibodies, and the new monoclonal antibodies 769A7, 769C5, and 770F7 may recognize some new epitopes
.
In order to specifically analyze the structural information of different epitopes bound to monoclonal antibodies to EBV gH/gL/gp42, the authors packaged and analyzed the X-ray crystal structure and electron density maps
of monoclonal antibody 769B10, 769C2 and 769F7 bound to EBV gH/gL/gp42 polypeptides, respectively.
In terms of crystal structure, the total buried surface area (BSA) of 769B10 bound to gH/gL/gp42 is 1074 Å2, which is an antigen supersite (antigenic supersite), which can identify both gH and gL
.
From the electron density map of negative dyeing electron microscopy, the position of 769B10 binding gH/gL/gp42 has a coincident region with monoclonal antibody CL40 and AMMO1, and the binding region of 769B10 and AMMO1 is close to the KGD integrin-binding motif on gH/gL, which can significantly hinder the connection
between gH/gL and integrin.
Monoclonal antibody 769C2 can bind the N-terminal and gL of gH at the same time, and the overall embedded surface area BSA is 941Å 2; The pattern of monoclonal antibody 769F8 binding gH/gL to 769C2 is similar and explainsThis is the reason for the competitive relationship between the
two.
In 2020, Yan Jinghua, a researcher at the Institute of Microbiology of the Chinese Academy of Sciences, analyzed the crystal structure of the ligand-recognition domain of EBV gH/gL and its receptor EphA2.
In this paper, by comparing the regions where EphA2, monoclonal antibody 769C2 and monoclonal antibody E1D1 bind to EBV gH/gL, it is found that the regions where monoclonal antibody 769C2 and monoclonal antibody E1D1 bind to gH/gL and the region where EphA2 and gH/gL are bound by Yan Jinghua's laboratory have a large proportion of overlap, and the overall embedded surface area coincidence region is greater than 500 Å2, but the binding regions of monoclonal antibody 769C2 and monoclonal antibody E1D1 are close but not overlapping.
There is no competition between the two
.
The large overlap between 769C2 and the region of receptor EphA2-binding gH/gL found a structural basis for 769C2 blocking EBV infection in epithelial cells, while the neutralization or blocking effect of 769C2 on EBV-infected B cells may be affected by the binding angle, steric hindrance or other mechanisms of the monoclonal antibody
.
The monoclonal antibody 770F7 binds to both EBV gH and gL, and the overall embedded surface area BSA is 1050Å 2
.
770F7 recognizes a new epitope of gH/gL, located at the C terminal of gH; The recognition of monoclonal antibody CL59 with gH/gL is also located at the C terminal of gH, but opposite the 770F7 recognition region
.
The 4th domain D-IV at the c-terminal of gH is critical for the fusion of EBV with cells, so monoclonal antibody 770F7 can play the role of
fusion inhibition.
Summarizing the crystal structure of monoclonal antibody and EBV gH/gL previously analyzed and newly analyzed in this paper, the authors further analyze the vulnerable sites
on gH/gL that are easily neutralized or easily blocked by fusion 。 According to the order of gH from N terminal to C terminus, gH/gL can be divided into 4 domains of D-I, D-II, D-III, and d-IV, and different antibodies can recognize 7 different antigen regions on gH/gL: 2 of them are located in D-I, that is, 769C2-770F8 antigen site and E1D1 antigen site; 2 are located in DI-II, respectively AMMO1, 769B10 and CL40 identified sites and 769A7 identified sites; In the DII-III domain, it contains 1 antigen site bound by 769C5 and 1D8; In the DIII-IV domain, CL59 and 770F7 recognize two antigenic loci located on opposite sides
.
These epitopes occupy 40% of the surface of gH/gL, while the region above the 770F7 epitope near the gp42 spherical domain, the region between CL59 epitope and 769C2 epitope has not yet identified antibodies that play a neutralizing or fusion blocking effect
.
Analyzing the structure of binding of other herpesvirus neutralizing antibodies to their gH/gL proteins, the authors found that the monoclonal antibodies VZV RC and VZV94 of varicella zoster virus VZV bind to VZV gH/gL in a location similar to the region where 769B10 or CL40 binds to EBV gH/gL.
The binding region of monoclonal antibody 13H11 to HCMV gH/gL of human cytomegalovirus HCMV is similar to the region of CL40 binding to EBV gH/gL, the region where 3G16 binds to HCMV gH/gL is similar to the region where CL59 binds to EBV gH/gL, and the location of monoclonal antibody 1-32 binding to HCMV gH/gL is similar to the binding region
of 769C2 to EBV gH/gL 。 However, EBV monoclonal antibodies are only specific for EBV gH/gL, and VZV and HCMV monoclonal antibodies cannot bind to EBV gH/gL; The position of neutralizing antibody binding corresponding to gH/gL is conserved, but the protein sequence of different viruses gH/gL is different.
The use of monoclonal antibodies to bind to the gH/gL region can provide a reference
for the development of different herpesvirus vaccines or therapeutic antibodies.
At the end of the full paper, the authors transferred human CD34+ hematopoietic stem cells to irradiated NOG mice to develop human lymphocytes, and conducted humanized mouse challenge and challenge protection tests
by intravenous infusion of monoclonal antibody and EBV 。 By evaluating the alleviation of mouse weight loss, the increase of mouse survival rate, the decrease of blood and tissue virus content, the decrease of lymphoma occurrence, and whether visible skin lesions occur, the protective effect
of monoclonal antibody on EBV infection was discussed.
The experiments found that the monoclonal antibodies 769C2 and 769B10 had a long half-life in mice, 769B10 and 770F7 treated mice significantly reduced EBV virus titers in tissues, and 769B10-treated mice had the lowest EBV virus titers in their blood and effectively eliminated the occurrence
of lymphoma in vaccinated mice.
The full text starts from the isolation and identification of blood monoclonal antibodies from healthy donors, the detection of monoclonal antibodies to EBV gH/gL neutralization and fusion inhibition, the structural basis of monoclonal antibodies to neutralize and fusion inhibition, the epitope characteristics of EBV gH/gL that are easily neutralized and easily inhibited by fusion, and the comparison of different herpesvirus gH/gL neutralization and fusion inhibitory sites by antibodies.
From the perspective of the protective power of monoclonal antibody in the EBV challenge test of humanized mice, the epitopes that are easily targeted and neutralized and inhibited by fusion when EBV invades infected cells with the help of gH/gL are comprehensively and systematically studied, which lays a solid foundation for the further development and application of preventive and therapeutic EBV vaccines or antibodies, and also sets a benchmark and paradigm for the development of structure-based vaccines and antibodies against other pathogens
.
The corresponding author of the article is Cohen from the NIH's National Institute of Allergy and Infectious Diseases (NIAID).
Professor JI and Professor
Joyce MG.
Professor Cohen JI is the head of the Department of Medical Virology at NIAID, with a research interest in the pathogenesis of human herpesvirus, as well as the development of vaccines and monoclonal antibodies against human
herpesvirus.
Another corresponding author, Professor Joyce MG, is also the director of the U.
S.
Army Research Institute of Wald Reed and the Henry Jackson Foundation for the Advancement of Military Medicine Laboratory of Emerging Infectious Diseases; He is a structural biologist whose research interests lie in the use of X-ray crystallography and electron microscopy to resolve the structure of viral antigen-antibody interactions, and the structural design of vaccines and small molecule inhibitors
.
In 2019, Cohen JI cloned the expression of monoclonal antibody 769B10 from donor blood with high neutralizing EBV antibody titers, and this time he used a similar method to identify a group of 6 monoclonal antibodies including 769B10, and together with Joyce MG, he used structural biology to elucidate the epitope characteristics
of EBV gH/gL protein that are easily neutralized and easily inhibited by fusion.
Original link: https://doi.
org/10.
1016/j.
immuni.
2022.
10.
003
Platemaker: Eleven
References
1.
Chen WH, et al.
Epstein-Barr virus gH/gL has multiple sites of vulnerability for virus neutralization and fusion inhibition.
Immunity 2022.
2.
Bu W, et al.
Immunization with components of the fusion apparatus elicits antibodies that neutralize Epstein-Barr virus in B cells and epithelial cells.
Immunity 2019.
3.
Sathiyamoorthy K, et al.
Structural basis for Epstein-Barr virus host cell tropism mediated by pg42 and gHgL entry glycoproteins.
Nature Communication 2016.
4.
Sathiyamoorthy K, et al.
Inhibition of EBV-mediated membrane fusion by anti-gHgL antibodies.
PNAS 2017.
5.
Snijder J, et al.
An antibody targeting the fusion machinery neutralizes dual-tropic infection and defines a site of vulnerability on Epstein-Barr virus.
Immunity 2018.
6.
Su C, et al.
Molecular basis of EphA2 recognition by gHgL from gamma-herpesviruses.
Nature Communication 2020.
7.
Zhu QY, et al.
A potent and protective human neutralizing antibody targeting a novel vulnerable site of Epstein-Barr virus.
Nature Communication 2021.
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