Infectious mononucleosis and Epstein-Barr virus

Epstein-Barr virus (EBV) is a gamma-herpesvirus that infects over 90% of the human population worldwide. It is usually transmitted between individuals in saliva, and establishes replicative infection within the oropharynx as well as life-long latent infection of B cells. Primary EBV infection generally occurs during early childhood and is asymptomatic. If delayed until adolescence or later, it can be associated with the clinical syndrome of infectious mononucleosis (also known as glandular fever or 'mono'), an illness characterised by fevers, pharyngitis, lymphadenopathy and malaise. EBV infection is also associated with the development of EBV-associated lymphoid or epithelial cell malignancies in a small proportion of individuals. This review focuses on primary EBV infection in individuals suffering from infectious mononucleosis. It discusses the mechanism by which EBV establishes infection within its human host and the primary immune response that it elicits. It describes the spectrum of clinical disease that can accompany primary infection and summarises studies that are leading to the development of a vaccine designed to prevent infectious mononucleosis.     

EBV与HCMV传染性单核细胞增多症患儿的实验室指标比较

目的观察EB病毒（EBV）与人类巨细胞病毒（HCMV）感染所致的传染性单核细胞增多症（IM）患儿超敏C-反应蛋白（hs-CRP）、白细胞（WBC）计数、嗜中性粒细胞比值（N）、异常淋巴细胞（异淋）、嗜异性抗体和血清酶的变化。方法选择70例确诊有EBV病毒感染且具备传染性单核细胞增多症临床特点的患儿（A组）进行实验室检测指标分析及总结;并与37例HCMV相关传染性单核细胞增多症患儿（B组）进行比较。结果与EB组（A组）比较,HCMV组（B组）感染患儿hs-CRP水平、肌酸激酶同功酶（CK-MB）、丙氨酸氨基转移酶（ALT）、外周血WBC计数、异型淋巴细胞增高程度较低（P〈0.05）,嗜异性抗体常为阴性,两组N值差异无统计学意义（P〉0.05）。结论 EBV与HCMV感染所致的传染性单核细胞增多症患儿的实验室指标变化不同,应重视IM患儿的实验室检查以辅助诊断。     

Severe Neutropenia in Infectious Mononucleosis

Mild neutropenia is a well-known concomitant of infectious mononucleosis caused by the Epstein-Barr virus (EBV) occurring in the first weeks of illness. However, severe neutropenia (less than 200 polymorphonuclear leukocytes per μl) is not generally regarded as a complication of infectious mononucleosis. Three patients were seen with severe neutropenia and EBV infection, and an additional eight cases were found in the literature. In two of the latter cases the neutropenia was fatal.In the 11 cases the severe neutropenia began 14 to 40 days after illness and usually lasted for three to seven days. At the time of severe neutropenia, studies of marrow specimens showed increased proportions of promyelocytes and myelocytes. Our data suggest that EBV infection is the proximate cause of the severe neutropenia in some patients with infectious mononucleosis and that in such cases close observation and early treatment of suspected superinfections is necessary.     

Infectious Mononucleosis and its Relationship to EB Virus Antibody: A JOINT INVESTIGATION BY UNIVERSITY HEALTH PHYSICIANS AND P.H.L.S. LABORATORIES

In October 1969 tests made on 1,457 students entering English universities and colleges showed that 57% already possessed antibody to EB virus. The students without antibody in these initial tests were retested seven months later and by then 12% had acquired antibody. In about one-third of them the acquisition of antibody was not associated with any illness. In about 20% respiratory and other illness had occurred, but these symptoms were almost equally frequent in students who had not acquired antibody. Nearly half had developed infectious mononucleosis. In students in whom the acquisition of EB virus antibody was associated with the clinical and haematological manifestations of infectious mononucleosis the Paul-Bunnell test was almost invariably positive. In contrast, when these manifestations were not associated with the acquisition of EB virus antibody the Paul-Bunnell test was always negative.Tests for cytomegalovirus antibody were also made on the students at entry. The proportion of students with this antibody was much less (30%) and only a small proportion (1·4%) of those without antibody had acquired cytomegalovirus antibody seven months later. In the only patient in whom the acquisition of cytomegalovirus antibody alone was associated with the clinical and haematological features of infectious mononucleosis the Paul-Bunnell test was negative.     

Serological Response of the EBV Antibodies in Pediatric Cases of Infectious Mononucleosis and in Their Contacts

The EBV antibodies were measured in 378 sera from a group of 129 pediatric and older cases of infectious mononucleosis and from 117 family and social contacts. Cases of infectious mononucleosis with only one exception were EBV seropositive in acute and/or convalescent sera. Fourteen cases, however, from whom no convalescent serum was available were EBV seronegative. A rise in EBV antibodies of two dilutions or more was demonstrated in 15 of the 129 cases. The prevalence of these antibodies in contacts reached 50 to 70% in each of four age groups. A significant antibody rise was encountered in only four cases, one of whom was found to have infectious mononucleosis simultaneously with the index case and one after an interdisease period of 10 months. The infectivity of the EB virus (and of infectious mononucleosis if causally related) and its horizontal transmission seem to be as low in nature as they appear to be experimentally in the laboratory.     

Evidence for early infection of nonneoplastic natural killer cells by Epstein-Barr virus

We examined lymph nodes and tonsils from patients with infectious mononucleosis by combined detection of EBV-encoded RNA and a specific marker of natural killer (NK) cells, PEN5. A small number of Epstein-Barr virus (EBV) latently infected nonneoplastic NK cells were detected. Our data demonstrate that NK cells are natural targets of EBV and that infection of these cells is an early event observed during primary EBV infection.     

Epstein-Barr virus infection in the neonatal period and in childhood

In an attempt to detect and characterize congenital, neonatal and early childhood EBV infections, a prospective sero-epidemiological study was undertaken in 112 newborn infants and their mothers, 25 additional newborns undergoing exchange transfusion, 114 randomly selected hospitalized infants aged 0 to 3 years, and 109 siblings and parents of these infants. Leukocyte culture was attempted in all the newborns and in 25 pre- and post-transfusion.The findings of EBV seroconversion in six patients without clearly apparent illness, infectious mononucleosis in only one case with significant EBV antibody rise, seroreversion in three cases in early childhood, higher newborn than maternal EBV antibody titres in three cases and the establishment of two permanent lymphoblastoid cell lines from newborns following exchange transfusion raise the possibility of abortive primary EBV infection in early life. Congenital or neonatal infections following exchange transfusions, however, could not be substantiated with certainty since the EBV antibodies did not persist at follow-up except possibly in two cases. Parenteral transmission of the EB virus by exchange transfusion at birth is probably prevented by the presence of EBV antibodies in either donor or recipient.     

Epstein-Barr virus and cytomegalovirus antibodies in infectious mononucleosis.

A method has been evolved for the demonstration of Epstein-Barr virus (EBV) and cytomegalovirus (CMV) infection in 83 cases of infectious mononucleosis. Serum samples were tested for EBV IgM, anti-VCA IgG, anti-EBNA, CMV IgM and CMV IgG antibodies. An acute-phase sample (or samples) and a convalescence sample were examined in each case, and in 44 cases an additional samples was examined 5-12 months after the illness. Since the different antibodies showed characteristic differences in both titre and persistence, a reliable serodiagnosis has become possible. Acute EBV infection is characterized by the presence of EBV-VCA IgG and EBV IgG antibodies and the lack of anti-EBNA. The latter becomes demonstrable as late as the 4th to 5th month after infection. Mean age of the patients was 19 years. EBV infection was demonstrated in 65%, CMV infection in 18% of the cases. In 12% double infection seemed to be probable.     

Cytotoxic CD4+ T-cells specific for EBV capsid antigen BORF1 are maintained in long-term latently infected healthy donors

Epstein Barr Virus (EBV) infects more than 95% of the population whereupon it establishes a latent infection of B-cells that persists for life under immune control. Primary EBV infection can cause infectious mononucleosis (IM) and long-term viral carriage is associated with several malignancies and certain autoimmune diseases. Current efforts developing EBV prophylactic vaccination have focussed on neutralising antibodies. An alternative strategy, that could enhance the efficacy of such vaccines or be used alone, is to generate T-cell responses capable of recognising and eliminating newly EBV-infected cells before the virus initiates its growth transformation program. T-cell responses against the EBV structural proteins, brought into the newly infected cell by the incoming virion, are prime candidates for such responses. Here we show the structural EBV capsid proteins BcLF1, BDLF1 and BORF1 are frequent targets of T-cell responses in EBV infected people, identify new CD8+ and CD4+ T-cell epitopes and map their HLA restricting alleles. Using T-cell clones we demonstrate that CD4+ but not CD8+ T-cell clones specific for the capsid proteins can recognise newly EBV-infected B-cells and control B-cell outgrowth via cytotoxicity. Using MHC-II tetramers we show a CD4+ T-cell response to an epitope within the BORF1 capsid protein epitope is present during acute EBV infection and in long-term viral carriage. In common with other EBV-specific CD4+ T-cell responses the BORF1-specific CD4+ T-cells in IM patients expressed perforin and granzyme-B. Unexpectedly, perforin and granzyme-B expression was sustained over time even when the donor had entered the long-term infected state. These data further our understanding of EBV structural proteins as targets of T-cell responses and how CD4+ T-cell responses to EBV change from acute disease into convalescence. They also identify new targets for prophylactic EBV vaccine development.     

Early Virological and Immunological Events in Asymptomatic Epstein-Barr Virus Infection in African Children

Epstein-Barr virus (EBV) infection often occurs in early childhood and is asymptomatic. However, if delayed until adolescence, primary infection may manifest as acute infectious mononucleosis (AIM), a febrile illness characterised by global CD8+ T-cell lymphocytosis, much of it reflecting a huge expansion of activated EBV-specific CD8+ T-cells. While the events of AIM have been intensely studied, little is known about how these relate to asymptomatic primary infection. Here Gambian children (14–18 months old, an age at which many acquire the virus) were followed for the ensuing six months, monitoring circulating EBV loads, antibody status against virus capsid antigen (VCA) and both total and virus-specific CD8+ T-cell numbers. Many children were IgG anti-VCA-positive and, though no longer IgM-positive, still retained high virus loads comparable to AIM patients and had detectable EBV-specific T-cells, some still expressing activation markers. Virus loads and the frequency/activation status of specific T-cells decreased over time, consistent with resolution of a relatively recent primary infection. Six children with similarly high EBV loads were IgM anti-VCA-positive, indicating very recent infection. In three of these donors with HLA types allowing MHC-tetramer analysis, highly activated EBV-specific T-cells were detectable in the blood with one individual epitope response reaching 15% of all CD8+ T-cells. That response was culled and the cells lost activation markers over time, just as seen in AIM. However, unlike AIM, these events occurred without marked expansion of total CD8+ numbers. Thus asymptomatic EBV infection in children elicits a virus-specific CD8+ T-cell response that can control the infection without over-expansion; conversely, in AIM it appears the CD8 over-expansion, rather than virus load per se, is the cause of disease symptoms.     

Human immune responses to synthetic peptides from the Epstein-Barr nuclear antigen

Humans infected with Epstein-Barr virus (EBV), the causative agent of infectious mononucleosis, develop antibodies against a nuclear antigen (EBNA) that is present in virally transformed B lymphocytes. The EBNA protein contains a unique glycine-alanine repeating sequence. We have synthesized peptides corresponding to various regions of the EBNA molecule within and near this sequence. Rabbit antibodies against the peptides within the sequence reacted directly with the EBNA protein, as detected by Western blotting. The sera of individuals with antibodies against Epstein-Barr virus contained abundant antibodies also reactive with one or several of the synthetic peptides within the sequence. Moreover, human antibodies against these simple peptides were induced specifically early in the course of infectious mononucleosis. When compared with normal controls, antibody levels to the glycine-alanine peptides were significantly higher in patients with rheumatoid arthritis and progressive systemic sclerosis, but not in patients with two other autoimmune diseases. These results document that i) antibodies against the peptides detect the EBNA protein, ii) humans infected with EBV produce high titers of antibodies reactive with these synthetic antigens, and iii) antibody titers against the peptides are abnormally elevated in certain autoimmune diseases.     

Epstein-Barr病毒的免疫调控与逃逸机制北大核心CSCD

EB病毒(Epstein-Barr Virus,EBV)属于γ疱疹病毒科,是第一个被发现与人类肿瘤相关的DNA病毒。EB病毒通过激活Toll样受体(Toll like receptors,TLRs)信号通路,诱导I型干扰素的大量释放和功能性的自噬机制,从而引起机体的免疫应答。然而,相对于其他疱疹病毒,EB病毒已进化出更为精细且错综复杂的机制来破坏和逃逸宿主的免疫系统,如限制自身蛋白表达、活化宿主的泛素-蛋白酶体系统、干扰或逆转自噬与泛素化修饰等。这些机制会引发EB病毒在宿主体内的持续性感染,导致宿主免疫功能失调,引发EB病毒相关疾病(如鼻咽癌、传染性单核细胞增多症等)。因此,研究EB病毒特异性的免疫调控机制不仅对深入理解EB病毒的潜伏性感染和致癌性至关重要,而且还将为EB病毒诱发的相关疾病的免疫预防与治疗鉴定出新的潜在靶点。此文主要阐述了EB病毒调控宿主免疫应答和逃逸先天免疫应答的分子机制。     

以儿童呼吸道感染为主的非典型EBV感染报道

目的报道儿童EBV感染所致的临床疾病谱与年龄特点,以进一步提高对EBV感染诊治水平.方法回顾性分析了EBV-VCA-IgM或EBV-DNA-PCR诊断的690例儿童EBV感染的疾病分布和年龄分布特点.结果EBV感染儿童非典型传染性单核细胞增多症患儿422例,占61.16%,非典型EBV感染268例,占38.84%.非典型EBV感染中以呼吸道感染最为多见,为191例,占非典型EBV感染的71.27%.其他为皮炎或口炎、血小板减少性紫癜、腹泻病、川畸病、肠系膜或颈淋巴结炎、肾炎或肾病和CNS感染等.EBV感染致传染性单核细胞增多症和呼吸道感染在各年龄组的分布差异无显著性,EBV感染男女比为1.79：1.结论儿童EBV感染所致疾病多样,累及系统多,非典型表现以呼吸道感染为主.传染性单核细胞增多症和呼吸道感染在各年龄组间差异无显著性.     

Cytomegalovirus in the mononucleosis syndrome in children

In 7 children aged 18 months to 7 years isolated from a group of 128 children with infectious mononucleosis the cytomegalovirus infection was found. Infection was diagnosed by determination of antibodies against immediate early and late CMV antigen by means of the ELISA test. Besides that, antibodies were determined against the capsid antigen and early antigen of EB virus by the method of indirect immunofluorescence. In four children only cytomegalovirus infection was found and three had a mixed infection with both viruses and the diagnosis in these cases was: infectious mononucleosis (due to EBV) with coexistent or following CMV infection. In the sera of two children with cytomegalovirus mononucleosis changes were observed in the antibodies against EBV which is explained as a result of interactions between CMV and EBV in the organism of the host.     

Hepatitis C virus and Epstein-Barr virus: dual infection or atypical antibody response

Positive serological reactions against hepatitis C virus (HCV) appeared in the course of Epstein-Barr virus (EBV) infectious mononucleosis. In 429 consecutive patients with high levels of transaminases, 28 patients with EBV primary infection were found. The presence of anti-HCV antibodies and HCV RNA was studied in these subjects. In seven patients anti-HCV antibodies (C33 and C22c RIBA bands) were detected, but all were polymerase chain reaction (PCR) negative. These results may have been due solely to a HCV infection or were an atypical response to HCV in the course of infectious mononucleosis.     

Genome of a mononucleosis Epstein-Barr virus contains DNA fragments previously regarded to be unique to Burkitt's lymphoma isolates

We wished to learn whether the genomes of strains of EMB isolated from patients with infectious mononucleosis are consistently distinguishable from those of strains from Burkitt's lymphoma. The genome of a new transforming strains (FF41) of EBV isolated from saliva of a patient with uncomplicated infectious mononucleosis was compared with the DNA of B95-8, the only other available virus from mononucleosis. It had been found previously that B95-8 has a deletion of about 8 Md in the region of the physical map represented by the Eco RI C, Hind III D, and Bam HI I fragments. The W91 and HR-1 isolates for Burkitt's lymphoma are not deleted in this region and it had been proposed that additional information was characteristic of EBV isolates from Burkitt's lymphoma. By means of restriction enzyme analysis, blot hybridization experiments and molecular cloning of FF41 DNA we demonstrate that the deletion found in B95-8 is not present in the new mononucleosis isolate. The FF41 genome contains an extra 8 Md of DNA, represented by Bam HI fragments B', W' and I', which are located in a larger Eco RI C fragment. Thus the genome of this salivary isolate contains DNA that had previously been regarded to be unique to strains from Burkitt's lymphoma. It is therefore unlikely that major insertions or deletions in the EBV genome account for differences in disease manifestation following EBV infection.     

Murine gammaherpesvirus 68: a model for the study of Epstein-Barr virus infections and related diseases

Epstein-Barr virus (EBV) is a ubiquitous human gammaherpesvirus (GHV) that causes acute infection and establishes life-long latency. EBV is associated with the development of B-cell lymphoproliferative disorders, several malignant cancers, the syndrome of infectious mononucleosis, and chronic interstitial lung disease. Although the molecular biology of EBV has been characterized extensively, the associated disease conditions and their pathogenesis are difficult to study in human populations because of variation in human environments and genetics, the well-documented effect of stressors on pathogenesis, and the chronic and latent properties of the virus. GHV are highly species-specific, and suitable animal models for EBV are not available. However, in 1980, a murine gammaherpesvirus (MuGHV, also known as MHV68 and gammaHV68) was identified as a natural pathogen of bank voles and wood mice. Experimental MuGHV infections in laboratory mice share many features of EBV infections in humans, including facets of the clinical human syndrome known as infectious mononucleosis. These features make MuGHV a valuable experimental model for studying the pathophysiology of a GHV in a natural host.     

Demonstration of EBNA (Epstein-Barr virus nuclear antigen) antibodies of different immunoglobulin classes.

Anit-EBNA IgM, a previously unknown antibody, was detected by the antihuman globulin anticomplement immunofluorescence (ACIF) method in serum samples from acute infectious mononucleosis (IM) of Epstein-Barr virus (EBV) origin. The antibody disappears from the serum in some weeks during convalescence. It was absent in anti-EBV=positive sera of healthy donors and in serum samples taken from patients with IM caused by cytomegalo-virus. The antibody appears simultaneously with anti-EBV IgmM and, reaching a lower titre than the latter, its titre curve runs parallel with the anti-EBV IgM curve. Since in acute EBV infections, anti-EBNA IgM always appeared, its presence may serve as an additional evidence of the acuteness of EBV infection. In EBV-seropositive healthy subjects, the bulk of antibodies belongs to the IgG class, non-complement-fixing IgA antibodies occur only sporadically.     

Epidemiologic studies assessing the role of the Epstein-Barr virus in Hodgkin's disease.

The hypothesis that an infection plays a role in the etiology of Hodgkin''s disease (HD) is suggested by both its clinical and histologic features. Its bimodal age-incidence pattern also suggests an infectious process among younger persons. In economically advantaged populations, the first peak occurs among young adults, while in disadvantaged populations, it occurs among children at a much lower frequency. It appears that the age distribution of HD shadows that of susceptibility to common childhood infections, such as the Epstein-Barr virus (EBV); furthermore, that risk of HD is increased among those susceptible to a relatively late infection, in parallel with infectious mononucleosis (IM), and it has been found that people who have had IM have about three times the expected rate of HD. Serologically, there is a consistent association between EBV and HD. As a group, patients have an altered antibody pattern against EBV which suggests chronic reactivation, both following and preceding diagnosis. This altered pattern is common to all age groups. Severity of infection may alter host control among younger people, while diminished cellular immunity with aging may allow similar reactivation among older persons. Whether the EBV plays a direct role or simply reflects the action of a more primary factor is unknown.