Kinetics of Epstein-Barr Virus (EBV) Neutralizing and Virus-Specific Antibodies after Primary Infection with EBV

Bu, Wei; Hayes, Gregory M.; Liu, Hui; Gemmell, Lorraine; Schmeling, David O.; Radecki, Pierce; Aguilar, Fiona; Burbelo, Peter D.; Woo, Jennifer; Balfour, Henry H.; Cohen, Jeffrey I.

doi:10.1128/cvi.00674-15

Cited by 39 publications

(36 citation statements)

References 31 publications

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“…gp350-binding antibodies were detected in the majority of individuals with AIM at symptom onset (Fig. 1A) and increased in titer from AIM through CONV, with the levels during CONV being similar to those in healthy, agematched EBV-seropositive donors; these findings are compatible with those of recently reported studies (20,29).…”

Section: Discussionsupporting

confidence: 82%

“…The lack of detectable EBV-specific neutralizing activity in Raji cell assays from samples collected during AIM is consistent with previously reported data from studies using either a similar assay (20) or a B-cell transformation assay (29). However, using a more sensitive PCR-based assay with primary B cells, we detected neutralizing antibody activity in the plasma of the majority (83%) of AIM patients.…”

Section: Discussionsupporting

confidence: 80%

“…The EBV enhanced green fluorescent protein (eGFP)-tagged Raji cell neutralization assay performs comparably to a previously used transformation assay (19,20). Using this assay, IgG neutralizing activity was not detected in any AIM patients (Fig.…”

Section: Resultsmentioning

confidence: 81%

“…A flow cytometry-based assay was used to measure the neutralization of infection of Raji cells with the eGFP-tagged Akata isolate (Akata-eGFP); this method has been adopted as a suitable substitute for the traditional primary B-cell transformation assay (19,20,48). Briefly, plasma IgG (10 l of a 1-mg/ml stock) was mixed with a known titer of virus and incubated for 1 h at 37°C.…”

Section: Methodsmentioning

confidence: 99%

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High Epstein-Barr Virus Load and Genomic Diversity Are Associated with Generation of gp350-Specific Neutralizing Antibodies following Acute Infectious Mononucleosis

Weiss

Alter

Ogembo

et al. 2017

J Virol

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The Epstein-Barr virus (EBV) gp350 glycoprotein interacts with the cellular receptor to mediate viral entry and is thought to be the major target for neutralizing antibodies. To better understand the role of EBV-specific antibodies in the control of viral replication and the evolution of sequence diversity, we measured EBV gp350-specific antibody responses and sequenced the gp350 gene in samples obtained from individuals experiencing primary EBV infection (acute infectious mononucleosis [AIM]) and again 6 months later (during convalescence [CONV]). EBV gp350-specific IgG was detected in the sera of 17 (71%) of 24 individuals at the time of AIM and all 24 (100%) individuals during CONV; binding antibody titers increased from AIM through CONV, reaching levels equivalent to those in age-matched, chronically infected individuals. Antibody-dependent cell-mediated phagocytosis (ADCP) was rarely detected during AIM (4 of 24 individuals; 17%) but was commonly detected during CONV (19 of 24 individuals; 79%). The majority (83%) of samples taken during AIM neutralized infection of primary B cells; all samples obtained at 6 months postdiagnosis neutralized EBV infection of cultured and primary target cells. Deep sequencing revealed interpatient gp350 sequence variation but conservation of the CR2-binding site. The levels of gp350-specific neutralizing activity directly correlated with higher peripheral blood EBV DNA levels during AIM and a greater evolution of diversity in gp350 nucleotide sequences from AIM to CONV. In summary, we conclude that the viral load and EBV gp350 diversity during early infection are associated with the development of neutralizing antibody responses following AIM.IMPORTANCE Antibodies against viral surface proteins can blunt the spread of viral infection by coating viral particles, mediating uptake by immune cells, or blocking interaction with host cell receptors, making them a desirable component of a sterilizing vaccine. The EBV surface protein gp350 is a major target for antibodies. We report the detection of EBV gp350-specific antibodies capable of neutralizing EBV infection in vitro. The majority of gp350-directed vaccines focus on glycoproteins from lab-adapted strains, which may poorly reflect primary viral envelope diversity. We report some of the first primary gp350 sequences, noting that the gp350 host receptor binding site is remarkably stable across patients and time. However, changes in overall gene diversity were detectable during infection. Patients with higher peripheral blood viral loads in primary infection and greater changes in viral diversity generated more efficient antibodies. Our findings provide insight into the generation of functional antibodies, necessary for vaccine development.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionsupporting

confidence: 80%

Section: Resultsmentioning

confidence: 81%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

High Epstein-Barr Virus Load and Genomic Diversity Are Associated with Generation of gp350-Specific Neutralizing Antibodies following Acute Infectious Mononucleosis

Weiss

Alter

Ogembo

et al. 2017

J Virol

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“…Antibody responses were assessed with the luciferase immunoprecipitation system (LIPS) assay (10). This assay has been used successfully in studies of human herpesviruses and other pathogens (11)(12)(13)(14)(15)(16) and does not require species-specific detection reagents, making it an excellent candidate for assessing Asian elephant antibody responses.…”

mentioning

confidence: 99%

Lethal Hemorrhagic Disease and Clinical Illness Associated with Elephant Endotheliotropic Herpesvirus 1 Are Caused by Primary Infection: Implications for the Detection of Diagnostic Proteins

Fuery

Pursell

Tan

et al. 2020

J Virol

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Elephant endotheliotropic herpesvirus (EEHV) can cause lethal hemorrhagic disease in juvenile Asian elephants, both in captivity and in the wild. Most deaths associated with the virus are caused by two chimeric variants of EEHV1 (EEHV1A and EEHV1B), while two other EEHVs endemic within Asian elephants (EEHV4 and EEHV5) have been recognized but cause death less often. Whether lethal EEHV infections are due to primary infection or reactivation of latent virus remains unknown, and knowledge of the anti-EEHV antibody levels in young elephants is limited. To close these gaps, we sought to develop a serologic assay capable of distinguishing among infections with different EEHVs using a luciferase immunoprecipitation system (LIPS) for antibody profiling and a panel of conserved EEHV recombinant proteins and proteins unique to EEHV1. The results showed that elephants dying from EEHV1 hemorrhagic disease or ill from EEHV infection were seronegative for the EEHV species that caused the disease or illness, indicating that the events were associated with primary infection rather than reactivation of latent virus. We also demonstrated that waning of EEHV1-specific antibodies can occur in the first 2 years of life, when a threshold protective level of antibody may be needed to prevent severe EEHV1-related disease. Use of the LIPS assay to identify putative “diagnostic” proteins would be a valuable asset in determining the EEHV immune status of young elephants and responses to candidate EEHV vaccines in the future. IMPORTANCE Whether clinical illness and deaths associated with elephant endotheliotropic herpesvirus (EEHV) infection result from primary infection or reactivation of latent virus is a longstanding question in the field. By applying a relatively new assay, the luciferase immunoprecipitation system (LIPS), combined with the genomic sequences of the viruses, we gained the insights and tools needed to resolve this issue. Our EEHV1-specific LIPS assay should be useful for assessing the vulnerability of elephant calves to infection with different EEHVs and evaluating antibody responses to anti-EEHV vaccines. A significant proportion of the Asian elephant population is under some form of human care. Hence, the ability to screen for EEHV immune status in elephant calves should have a major impact on the management of these animals worldwide.

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Vaccine Development for Epstein-Barr Virus

Cohen

2018

Advances in Experimental Medicine and Biology

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107

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Epstein-Barr virus (EBV) is the primary cause of infectious mononucleosis and is associated with several malignancies, including nasopharyngeal carcinoma, gastric carcinoma, Hodgkin lymphoma, Burkitt lymphoma, and lymphomas in immunocompromised persons, as well as multiple sclerosis. A vaccine is currently unavailable. While monomeric EBV gp350 was shown in a phase 2 trial to reduce the incidence of infectious mononucleosis, but not the rate of EBV infection, newer formulations of gp350 including multimeric forms, viruslike particles, and nanoparticles may be more effective. A vaccine that also includes additional viral glycoproteins, lytic proteins, or latency proteins might improve the effectiveness of an EBV gp350 vaccine. Clinical trials to determine if an EBV vaccine can reduce the rate of infectious mononucleosis or posttransplant lymphoproliferative disease should be performed. The former is important since infectious mononucleosis can be associated with debilitating fatigue as well as other complications, and EBV infectious mononucleosis is associated with increased rates of Hodgkin lymphoma and multiple sclerosis. A vaccine to reduce EBV posttransplant lymphoproliferative disease would be an important proof of principle to prevent an EBV-associated malignancy. Trials of an EBV vaccine to reduce the incidence of Hodgkin lymphoma, multiple sclerosis, or Burkitt lymphoma would be difficult but feasible.

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Kinetics of Epstein-Barr Virus (EBV) Neutralizing and Virus-Specific Antibodies after Primary Infection with EBV

Cited by 39 publications

References 31 publications

High Epstein-Barr Virus Load and Genomic Diversity Are Associated with Generation of gp350-Specific Neutralizing Antibodies following Acute Infectious Mononucleosis

High Epstein-Barr Virus Load and Genomic Diversity Are Associated with Generation of gp350-Specific Neutralizing Antibodies following Acute Infectious Mononucleosis

Lethal Hemorrhagic Disease and Clinical Illness Associated with Elephant Endotheliotropic Herpesvirus 1 Are Caused by Primary Infection: Implications for the Detection of Diagnostic Proteins

Vaccine Development for Epstein-Barr Virus

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