Human Epstein-Barr Virus Infection Research Articles

NKT cells depend on SAP

An intracellular adaptor protein is indispensable for the development of natural killer T (NKT) cells, according to Pasquier et al. (page 695). The loss of these cells might contribute to the genesis of a lethal immunodeficiency syndrome. The adaptor protein in question—SAP (SLAM-associated protein)—is expressed in T, NK, and NKT cells and responds to SLAM family receptors by recruiting and activating the downstream tyrosine kinase Fyn. Fyn was known to be required for NKT cell development in the thymus, but the upstream cell surface signals remained unknown. Pasquier and colleagues now implicate the SLAM family of receptors in NKT cell development by showing that the loss of SAP results in a complete absence of NKT cells in both mice and humans. SAP-transmitted signaling events were uniquely required for the development of NKT cells, as conventional T cells and NK cells developed normally in the absence of SAP. The need for SAP-mediated signals may reflect the unique requirements for positive selection of NKT cells in the thymus. Whereas conventional T cells interact with thymic epithelial cells for selection, NKT cells must interact with CD1d-expressing thymocytes via their invariant T cell receptors. This unique interaction might also provide the required SLAM-mediated signals. In an intriguing twist, mutations in SAP cause a fatal disease called X-linked lymphoproliferative syndrome (XLP), which is characterized by uncontrolled Epstein-Barr virus (EBV) infections and B cell lymphomas. The loss of SAP impacts the function of multiple cell types including NK cells and T cells, but based on the current study, NKT cells may also contribute to XLP. Studying NKT cell activation during human EBV infection may give clues about why the lack of SAP, which results in so many immune cell defects, would preferentially increase susceptibility to only one type of virus.

Epidemiology of herpesvirus papio infection in a large captive baboon colony: similarities to Epstein-Barr virus infection in humans.

The epidemiology of herpesvirus papio, a lymphocryptovirus similar to Epstein-Barr virus (EBV), was studied in a captive colony of >1900 baboons. Herpesvirus papio IgG antibody titers were measured by IFA. In total, 438 specimens from 296 baboons were assessed, including 116 serial specimens from 52 juveniles and 6 infants studied monthly for 1 year following birth and at age 18 months. Maternally derived antibody reached a nadir at 4 months of age. About 75% of animals at 12 months of age and >95% of animals after age 24 months demonstrated serologic evidence of herpesvirus papio infection. After age 3 years, the geometric mean titer was 1:60-75. The epidemiology of herpesvirus papio infection in baboons closely parallels that of EBV infection in humans. An animal model of lymphocryptovirus infection will facilitate investigations of human lymphocryptovirus biology.

Inhibition of antigen presentation by the glycine/alanine repeat domain is not conserved in simian homologues of Epstein-Barr virus nuclear antigen 1.

Most humans and Old World nonhuman primates are infected for life with Epstein-Barr virus (EBV) or closely related gammaherpesviruses in the same lymphocryptovirus (LCV) subgroup. Several potential strategies for immune evasion and persistence have been proposed based on studies of EBV infection in humans, but it has been difficult to test their actual contribution experimentally. Interest has focused on the EBV nuclear antigen 1 (EBNA1) because of its essential role in the maintenance and replication of the episomal viral genome in latently infected cells and because EBNA1 endogenously expressed in these cells is protected from presentation to the major histocompatibility complex class-I restricted cytotoxic T-lymphocyte (CTL) response through the action of an internal glycine-alanine repeat (GAR). Given the high degree of biologic conservation among LCVs which infect humans and Old World primates, we hypothesized that strategies essential for viral persistence would be well conserved among viruses of this subgroup. We show that the rhesus LCV EBNA1 shares sequence homology with the EBV and baboon LCV EBNA1 and that the rhesus LCV EBNA1 is a functional homologue for EBV EBNA1-dependent plasmid maintenance and replication. Interestingly, all three LCVs possess a GAR domain, but the baboon and rhesus LCV EBNA1 GARs fail to inhibit antigen processing and presentation as determined by using three different in vitro CTL assays. These studies suggest that inhibition of antigen processing and presentation by the EBNA1 GAR may not be an essential mechanism for persistent infection by all LCV and that other mechanisms may be important for immune evasion during LCV infection.

The complexity of the Epstein-Barr virus infection in humans.

The Epstein-Barr virus (EBV) was isolated 40 years ago from cultures of Burkitt lymphoma cells (BL). The tumor was encountered in Africa and exhibited characteristical geographical, clinical and pathological features. Serological studies revealed that the virus is ubiquitous in humans. The primary infection is often accompanied by the syndrome of acute infectious mononucleosis (IM). It can induce malignant proliferation of B lymphocytes in conditions of immunodeficiency. EBV can immortalize B lymphocytes in culture. These cells carry the virus as episomes and express 9 virally encoded proteins. Their immunological recognition constitutes the surveillance which is responsible for the healthy virus carrier state. The main virus reservoir is represented by a low number of resting B lymphocyte which contain the viral genome but do not express its transformation proteins. The viral genome is detectable in all African BLs, in variable proportions of nasopharyngeal carcinoma, Hodgkin's disease, T cell lymphoma, lymphoepithelial like carcinoma, gastric carcinoma and leiomyosarcoma cases. The role of EBV in the genesis of these tumors is unknown.

An animal model for acute and persistent Epstein-Barr virus infection.

Epstein-Barr virus (EBV) is a human lymphocryptovirus that causes infectious mononucleosis, persists asymptomatically for life in nearly all adults, and is associated with the development of B cell lymphomas and nasopharyngeal carcinomas. A highly similar rhesus lymphocryptovirus naturally endemic in rhesus monkeys was used to orally infect naïve animals from a pathogen-free colony. This animal model reproduced key aspects of human EBV infection, including oral transmission, atypical lymphocytosis, lymphadenopathy, activation of CD23(+) peripheral blood B cells, sustained serologic responses to lytic and latent EBV antigens, latent infection in the peripheral blood, and virus persistence in oropharyngeal secretions. This system may be useful for studying the pathogenesis, prevention, and treatment of EBV infection and associated oncogenesis.

T Cell Receptor-Bearing Lymphocytes during Epstein-Barr Virus Infection

Lymphocytes bearing gamma delta T cell receptors (TCR) constitute a minor subpopulation of human peripheral blood lymphocytes. Their role and function during microbial infections are largely unknown. In 10 patients with Epstein-Barr virus-induced infectious mononucleosis, the gamma delta TCR-expressing T cell population expanded during the acute phase. These cells were largely delta TCS1-, CD4-, and CD8- but expressed activation antigens such as human leukocyte antigen-DR and CD38. The convalescent phase of infectious mononucleosis was characterized by a relative persistence of gamma delta T cells. Together these data suggest a possible role of gamma delta T cells in the control of primary Epstein-Barr virus infection in humans.

Lymphocytes activated by the Epstein-Barr virus to produce immunoglobulin do not express CD23 or become immortalized.

Epstein-Barr virus causes polyclonal activation and immortalization of a small percentage of peripheral blood B lymphocytes after in vitro infection. However, the susceptible B lymphocytes have not been identified. We have used the B lymphocyte activation antigen, CD23, as a marker for separating immortalized and non-immortalized Epstein-Barr virus-infected B lymphocytes and have identified the polyclonally-activated cells, using double staining for cytoplasmic immunoglobulin and viral antigens. The vast majority of cells expressing cytoplasmic immunoglobulin are negative for CD23 and for Epstein-Barr virus nuclear antigen, and are non-immortalized. Conversely, the CD23-positive, immortalized population are positive for Epstein-Barr virus nuclear antigen and negative for cytoplasmic immunoglobulin. These results define a diversity in the response of B lymphocytes to Epstein-Barr virus infection and suggest separate pathways for terminal differentiation and immortalization. This diversity may be important in determining the outcome of Epstein-Barr virus infection in humans.

Hematologic Consequences of Epstein-Barr Virus Infection

This article reviews the immunobiology of Epstein-Barr Virus infection in humans. It details the effects of this ubiquitous herpesvirus on the hematopoietic and lymphoreticular systems.

Heterogeneity of immune defects in three children with a chronic active Epstein-Barr virus infection.

Three children, all girls, showed long-lasting clinical and serologic evidence of chronic active Epstein-Barr virus (EBV) infection. Extremely high serum titers of IgG- and IgA-type VCA antibodies and EA antibodies were present, whereas EBNA antibody titers were in the range of those found in seropositive individuals. All three patients repeatedly showed the presence of nonspecific pokeweed mitogen (PWM)-activatable suppressor cells in the peripheral blood. The analysis of EBV-specific cytotoxic T cells showed that one patient exhibited normal cytotoxicity, whereas a second patient demonstrated no EBV-specific cytotoxicity together with unusually high levels of virus-infected B cells in the blood and lymph node. The third patient repeatedly showed refractoriness of the circulating B cells to EBV infection, probably on the basis of some developmental defect. It was concluded that each patient has his or her own peculiar defect in the virus-host balance, indicating that heterogeneity may underlie the syndrome of chronic active EBV infection in humans.

Herpesvirus sylvilagus infects both B and T lymphocytes in vivo.

Herpesvirus sylvilagus infection of cottontail rabbits (Sylvilagus floridanus) was studied as a model of herpesvirus-induced lymphoproliferative disorders. Leukocytosis, splenomegaly, proliferation of T cells and virus production by lymphocytes characterized this infectious mononucleosis-like disease. Approximately two copies of circular herpesvirus sylvilagus genomes per cell were detected in spleen cells at 2 weeks postinfection, and circular genomes could still be observed after 4 months. Circular viral genomes were found in both B and T lymphocytes. Small amounts of linear viral DNA (0.1 to 0.3 copies per cell) were also detected in both B and T cells. These results indicated that the virus did not replicate in the majority of lymphocytes in vivo. Herpesvirus sylvilagus infection in cottontail rabbits could be useful as a model for studying the complex virus-host relationships of lymphotropic herpesviruses and perhaps as an animal model for Epstein-Barr virus infection in humans.