SUMMARY: Epstein-Barr virus (EBV) is a gammaherpesvirus that infects a large fraction of the human population. Primary infection is often asymptomatic but results in lifelong infection, which is kept in check by the host immune system. In some cases, primary infection can result in infectious mononucleosis. Furthermore, when host-virus balance is not achieved, the virus can drive potentially lethal lymphoproliferation and lymphomagenesis. In this review, we describe the biology of EBV and the host immune response. We review the diagnosis of EBV infection and discuss the characteristics and pathogenesis of infectious mononucleosis. These topics are approached in the context of developing therapeutic and preventative strategies.

Background. University students were studied prospectively to determine the incidence of and risk factors for acquisition of primary Epstein–Barr virus (EBV) infection and the virologic and immune correlates of disease severity. Methods. EBV antibody–negative freshmen participated in monthly surveillance until graduation. If antibodies developed, proximate samples were assayed for viral load by polymerase chain reaction. Lymphocyte and natural killer (NK) cell numbers and activation were measured by flow cytometry, and plasma cytokine levels were measured by a multiplex assay. Results. Of 546 students screened, 202 (37%) were antibody negative; 143 antibody-negative students were enrolled. During a median of 3 years of observation, 66 subjects experienced primary infection. Of these, 77% had infectious mononucleosis, 12% had atypical symptoms, and 11% were asymptomatic. Subjects reporting deep kissing with or without coitus had the same higher risk of infection than those reporting no kissing (P < .01). Viremia was transient, but median oral shedding was 175 days. Increases were observed in numbers of NK cells and CD8⁺ T-cells but not in numbers of CD4⁺ T-cells during acute infection. Severity of illness correlated positively with both blood EBV load (P = .015) and CD8⁺ lymphocytosis (P = .0003). Conclusions. Kissing was a significant risk for primary EBV infection. A total of 89% of infections were symptomatic, and blood viral load and CD8⁺ lymphocytosis correlated with disease severity.

Infectious mononucleosis is a clinical entity characterized by pharyngitis, cervical lymph node enlargement, fatigue and fever, which results most often from a primary Epstein–Barr virus (EBV) infection. EBV, a lymphocrytovirus and a member of the γ‐herpesvirus family, infects at least 90% of the population worldwide, the majority of whom have no recognizable illness. The virus is spread by intimate oral contact among adolescents, but how preadolescents acquire the virus is not known. During the incubation period of approximately 6 weeks, viral replication first occurs in the oropharynx followed by viremia as early as 2 weeks before onset of illness. The acute illness is marked by high viral loads in both the oral cavity and blood accompanied by the production of immunoglobulin M antibodies against EBV viral capsid antigen and an extraordinary expansion of CD8⁺ T lymphocytes directed against EBV‐infected B cells. During convalescence, CD8⁺ T cells return to normal levels and antibodies develop against EBV nuclear antigen‐1. A typical clinical picture in an adolescent or young adult with a positive heterophile test is usually sufficient to make the diagnosis of infectious mononucleosis, but heterophile antibodies are not specific and do not develop in some patients especially young children. EBV‐specific antibody profiles are the best choice for staging EBV infection. In addition to causing acute illness, long‐term consequences are linked to infectious mononucleosis, especially Hodgkin lymphoma and multiple sclerosis. There is no licensed vaccine for prevention and no specific approved treatment. Future research goals are development of an EBV vaccine, understanding the risk factors for severity of the acute illness and likelihood of developing cancer or autoimmune diseases, and discovering anti‐EBV drugs to treat infectious mononucleosis and other EBV‐spurred diseases.

Background. Data on the age-specific prevalence of Epstein–Barr virus (EBV) infection are relevant for determining when to administer a prophylactic vaccine. Comparison of demographic groups could identify factors associated with its acquisition. Methods. The National Health and Nutrition Examination Surveys (NHANES) examine a representative sample of the US population. Serum specimens from NHANES participants 6–19 years old were tested for EBV antibody by enzyme immunoassay (EIA). A random portion was also tested by indirect immunofluorescence (IFA). Prevalence estimates and risk-factor comparisons used demographic data and sampling weights in logistic regression models. Results. Serum specimens collected between 2003 and 2010 from 9338 individuals participating in NHANES were tested. The concordance between EIA and IFA findings was 96.7%. The overall age-adjusted EBV antibody prevalence declined from 72% in 2003–2004 to 65% in 2009–2010 (P = .027). The prevalence in 2009–2010 by age group was as follows: 6–8 years, 50%; 9–11 years, 55%; 12–14 years, 59%; 15–17 years, 69%; and 18–19 years, 89%. Within each race/ethnicity group, younger age, health insurance coverage, higher household income, and education level were significantly associated with a lower prevalence of EBV antibody. Conclusions. The EBV antibody prevalence declined in US individuals aged 6–19 years from 2003–2004 to 2009–2010, mainly because of the decrease among non-Hispanic white participants. The declining antibody prevalence over time and the consistently high observed prevalence among participants aged 12–19 years support broad use of EBV vaccine before 12 years of age.

Infectious mononucleosis is a clinical entity characterized by sore throat, cervical lymph node enlargement, fatigue, and fever most often seen in adolescents and young adults and lasting several weeks. It can be caused by a number of pathogens, but this chapter only discusses infectious mononucleosis due to primary Epstein–Barr virus (EBV) infection. EBV is a γ-herpesvirus that infects at least 90 % of the population worldwide. The virus is spread by intimate oral contact among teenagers and young adults. How preadolescents acquire the virus is not known. A typical clinical picture with a positive heterophile test is usually sufficient to make the diagnosis, but heterophile antibodies are not specific and do not develop in some patients. EBV-specific antibody profiles are the best choice for staging EBV infection. In addition to causing acute illness, there can also be long-term consequences as the result of acquisition of the virus. Several EBV-related illnesses occur including certain cancers and autoimmune diseases, as well as complications of primary immunodeficiency in persons with the certain genetic mutations. A major obstacle to understanding these sequelae has been the lack of an efficient animal model for EBV infection, although progress in primate and mouse models has recently been made. Key future challenges are to develop protective vaccines and effective treatment regimens.