Infectious mononucleosis and B-cell transformation in response to infection with Epstein-Barr virus (EBV) is dependent upon binding of the EBV envelope glycoprotein gp350 to CD21 on B-cells. Gp350-specific antibody comprises most of the EBV neutralizing activity in the serum of infected patients, making this protein a promising target antigen for a prophylactic EBV vaccine. We describe a novel, tetrameric gp350-based vaccine that exhibits markedly enhanced immunogenicity relative to its monomeric counterpart. Plasmid DNA was constructed for synthesis, within transfected CHO cells, of a tetrameric, truncated (a.a. 1-470) gp350 protein (gp350(1-470)). Tetrameric gp350(1-470) induced ~20-fold higher serum titers of gp350(1-470)-specific IgG and >19-fold enhancements in neutralizing titers at the highest dose, and was >25-fold more immunogenic on a per-weight basis than monomeric gp350(1-470). Further, epidermal immunization with plasmid DNA encoding gp350(1-470) tetramer induced 8-fold higher serum titers of gp350(1-470)-specific IgG relative to monomer. Tetrameric gp350(1-470) binding to human CD21 was >24-fold more efficient on a per-weight basis than monomer, but neither tetramer nor monomer mediated polyclonal human B-cell activation. Finally, the introduction of strong, universal tetanus toxoid (TT)-specific CD4+ T-cell epitopes into the tetrameric gp350(1-470) had no effect on the gp350(1-470)-specific IgG response in naïve mice, and resulted in suppressed gp350(1-470)-specific IgG responses in TT-primed mice. Collectively, these data suggest that tetrameric gp350(1-470) is a potentially promising candidate for testing as a prophylactic EBV vaccine, and that protein multimerization, using the approach described herein, is likely to be clinically relevant for enhancing the immunogenicity of other proteins of vaccine interest.

The primary infection of Epstein-Barr virus (EBV) may results in hemophagocytic syndrome, known as EBV-associated hemophagocytic syndrome (EBV-AHS), but the clinical risk factors complicating this fatal disease in children with infectious mononucleosis (IM) are unknown. The aim of this study was to identify clinical features of EBV-AHS and to evaluate the curative effect of HLH-2004 protocol. The clinical and laboratory data of 644 IM children including 27 children developed into EBV-AHS and 43 HPS children associated with other diseases were retrospectively analyzed and logistic regression was used to identify the clinical risk factors complicating EBV-AHS. The results showed as follows: (1) the prevalence of EBV-AHS in IM children was 4.2% (27/644), and the prevalence in group aged younger than 3 years was higher than in other age groups. The incidence age of EBV-AHS was significantly younger than that of other HPS patients; (2) Liver function damage of group aged older than 7 years was much more severe in HPS patients. (3) Compared with other HPS patients, male patients were more common and liver function damage was severe in EBV-AHS patients, especially in the patients aged at 2 years or yanger. (4) The fatality rate in the EBV-AHS patients was 37.0% (10/27). (5)After treatment with HLH-2004 protocol, the fatality rate in patients with EBV-AHS decreased from 50.0% to 18.2%, the overall survival (OS) of 3 years significantly increased (P = 0.032). It is concluded that IM is a benign self-limited disease, of which only about 4.2% patients will develop into EBV-AHS. Clinical risk factors identified in this study may be helpful for early diagnosis of IM children with complicated EBV-ASH, the HLH-2004 protocol can obviously improve prognosis of EBV-HPS.

Epstein-Barr virus (EBV) is the major cause of infectious mononucleosis and is associated with several malignancies including nasopharyngeal carcinoma, gastric carcinoma, Hodgkin lymphoma, Burkitt lymphoma, and lymphoma after organ or stem cell transplant. A candidate vaccine containing soluble EBV glycoprotein gp350 protected cottontop tamarins from EBV lymphoma after challenge with EBV. In the only phase 2 trial of an EBV vaccine in humans, soluble gp350 in alum and monophosphoryl lipid A adjuvant reduced the rate of infectious mononucleosis in EBV seronegative adults, but did not affect the rate of EBV infection. A peptide vaccine corresponding to EBV latency proteins has been tested in a small number of adults to prevent infectious mononucleosis. Some of the barriers to development of an EBV vaccine include (a) whether viral proteins in addition to gp350 would be more effective for preventing mononucleosis or EBV malignancies, (b) the difficulty of performing clinical trials to prevent EBV associated malignancies in the absence of good surrogate markers for tumor development, and the long period of time between primary EBV infection and development of many EBV tumors, (c) the lack of knowledge of immune correlates for protection against EBV infection and disease, (d) the limitations in animal models to study protection against EBV infection and disease, and (e) the need for additional information on the economic and societal burden of infectious mononucleosis to assess the cost-benefit of a prophylactic vaccine.

Cerebellar ataxia is a common neurological presentation. It can be acute, subacute or chronic. Neurological complications of Epstein-Barr virus (EBV) are well-recognised with a variety of presentations. Acute cerebellar ataxia is a rare, but an established complication. It has been described as the sole manifestation of EBV infection without the systemic features of infectious mononucleosis. The pathophysiology is not clear. The course of the illness may last for a few months with a benign outcome, though serious complications can happen. We present a case of a 38-year-old man who presented with an acute cerebellar ataxia owing to EBV infection, along with a review of the literature.

It has long been known that multiple sclerosis (MS) is associated with an increased Epstein-Barr virus (EBV) seroprevalence and high immune reactivity to EBV and that infectious mononucleosis increases MS risk. This evidence led to postulate that EBV infection plays a role in MS etiopathogenesis, although the mechanisms are debated. This study was designed to assess the prevalence and magnitude of CD8+ T-cell responses to EBV latent (EBNA-3A, LMP-2A) and lytic (BZLF-1, BMLF-1) antigens in relapsing-remitting MS patients (n = 113) and healthy donors (HD) (n = 43) and to investigate whether the EBV-specific CD8+ T cell response correlates with disease activity, as defined by clinical evaluation and gadolinium-enhanced magnetic resonance imaging. Using HLA class I pentamers, lytic antigen-specific CD8+ T cell responses were detected in fewer untreated inactive MS patients than in active MS patients and HD while the frequency of CD8+ T cells specific for EBV lytic and latent antigens was higher in active and inactive MS patients, respectively. In contrast, the CD8+ T cell response to cytomegalovirus did not differ between HD and MS patients, irrespective of the disease phase. Marked differences in the prevalence of EBV-specific CD8+ T cell responses were observed in patients treated with interferon-β and natalizumab, two licensed drugs for relapsing-remitting MS. Longitudinal studies revealed expansion of CD8+ T cells specific for EBV lytic antigens during active disease in untreated MS patients but not in relapse-free, natalizumab-treated patients. Analysis of post-mortem MS brain samples showed expression of the EBV lytic protein BZLF-1 and interactions between cytotoxic CD8+ T cells and EBV lytically infected plasma cells in inflammatory white matter lesions and meninges. We therefore propose that inability to control EBV infection during inactive MS could set the stage for intracerebral viral reactivation and disease relapse.

Virus-specific CD4(+) T cells are key orchestrators of host responses to viral infection yet, compared with their CD8(+) T cell counterparts, remain poorly characterized at the single cell level. Here we use nine MHC II-epitope peptide tetramers to visualize human CD4(+) T cell responses to Epstein-Barr virus (EBV), the causative agent of infectious mononucleosis (IM), a disease associated with large virus-specific CD8(+) T cell responses. We find that, while not approaching virus-specific CD8(+) T cell expansions in magnitude, activated CD4(+) T cells specific for epitopes in the latent antigen EBNA2 and four lytic cycle antigens are detected at high frequencies in acute IM blood. They then fall rapidly to values typical of life-long virus carriage where most tetramer-positive cells display conventional memory markers but some, unexpectedly, revert to a naive-like phenotype. In contrast CD4(+) T cell responses to EBNA1 epitopes are greatly delayed in IM patients, in line with the well-known but hitherto unexplained delay in EBNA1 IgG antibody responses. We present evidence from an in vitro system that may explain these unusual kinetics. Unlike other EBNAs and lytic cycle proteins, EBNA1 is not naturally released from EBV-infected cells as a source of antigen for CD4(+) T cell priming.

Epstein-Barr virus (EBV) is a human herpesvirus that infects nearly all humans by adulthood and is associated with a spectrum of human diseases including Infectious Mononucleosis, Hodgkin Lymphoma, Nasopharyngeal Carcinoma, and lymphomas in immunosuppressed hosts. Nonhuman primate (NHP) animal models provide important experimental systems for studying EBV infection. There has been significant progress in studies of EBV-related herpesviruses, or lymphocryptoviruses (LCV), that naturally infect New and Old World NHPs. Prototypes for New and Old World LCV have been cloned and sequenced, humoral and cellular immune responses to LCV in NHP have been characterized, experimental LCV infections in naïve rhesus macaques have been successful, and a genetic system to manipulate specific viral genes in rhesus LCV (rhLCV) has been developed. These advances have led to new insights in the dynamic interactions with the host during acute and persistent EBV infection and can provide a novel platform for EBV vaccine development. Further development and utilization of the rhLCV animal model would be greatly enhanced by expansion of LCV-free breeding colonies as a reliable source of naïve animals for experimental studies. NHP animal models for EBV infection provide unique opportunities for understanding the biology of EBV infection in humans and translating that knowledge into effective vaccines against EBV-induced diseases.

We present a unique case of infectious mononucleosis attended with transient asymptomatic BK virus (BKV) manifestation in the urine of an immunocompetent caucasian boy without kidney dysfunction. The urine sediment showed abundant decoy cells initially misdiagnosed as malignant cancer cells. This case demonstrates that the occurrence of polyoma-BKV bearing decoy cells is self-limiting and not necessarily associated with overt kidney disease in an immunocompetent child. The shedding of decoy cells into the urine might be promoted by viral co-infections modulating the host's immune response such as infectious mononucleosis.

The Epstein-Barr virus early antigen (EBV EA) complex consists of multiple proteins with potential significance for diagnosis of EBV-related diseases. In many individuals, detection of antibody to the early antigen (EA) is a sign of active infection, but 20% of healthy people may have this antibody for years. We studied the role of EA immunoglobulin G (IgG) in individuals with atypical antibody responses in the diagnosis of infectious mononucleosis (IM) and in EBV-infected transplant patients. EA IgG was present in 72% of confirmed IM patients. A trend was observed between high viral loads and the presence of EA IgG and between low viral loads and the absence of EA IgG in EBV-associated disease negative liver transplant recipients. Three assays that measure serum EA IgG were compared; enzyme-linked immunosorbent assay (ELISA), chemiluminescent immunoassay (CLIA), and immunoblot assay. The automated CLIA was found to be more accurate than the ELISA when using the immunoblot assay as a "gold standard" assay in the detection of EA IgG. There may be a potential role for EA IgG testing, together with EBV viral load, in the prediction of transplant recipients at risk of EBV-associated disease; however, EA IgG does not play a significant role in the differential diagnosis of EBV infection in immunocompetent individuals.

Primary Epstein-Barr virus (EBV) infection occurs mainly in adolescents and young adults, with more than 90% of adults having serological evidence of past infection. Primary infection in those over the age of 40 is associated with an atypical and often more severe presentation that can lead to more extensive and invasive, and often unnecessary, diagnostic testing. The incidence of severe EBV-related illness in older adults has been observed to be increasing in industrialized nations. The characteristic presentation of infectious mononucleosis (IM) syndrome in elderly patients (age > 65) is not clearly defined in the literature. Here, we describe a case of primary EBV infection in an 80-year-old female and review the literature regarding primary seroconversion in elderly patients.