Control Of Epstein-Barr Virus Infection Research Articles

EB virus infection and the immune response

Epstein-Barr virus infects widely, and has a powerful ability to transfrom into a number of malignant diseases. The infection is mostly latent, without any obvious clinical symptoms. At present, more and more researches have found that cell-mediated immunity,especially T lymphocyte response plays an important role in the control of Epstein-Barr virus infection. Key words: Epstein-Barr virus; Immune response; Cell-mediated immunity

T Cell–Mediated Control of Epstein‐Barr Virus Infection in Humanized Mice

Humanized NOD/Shi-scid/interleukin-2Rgamma(null) (NOG) mice with full T cell development had significantly longer life span after Epstein-Barr virus (EBV) infection, compared with those with minimal T cell development. Removing CD3(+) or CD8(+) T cells from EBV-infected humanized mice by administration of anti-CD3 or anti-CD8 antibodies reduced their life span. CD8(+) T cells obtained from EBV-infected mice suppressed the outgrowth of autologous B cells isolated from uninfected mice and inoculated with EBV in vitro. These results indicate that humanized NOG mice are capable of T cell-mediated control of EBV infection and imply their usefulness as a tool to evaluate immunotherapeutic and prophylactic strategies for EBV infection.

Quantitative PCR for Epstein–Barr virus DNA and RNA in multiple sclerosis

Background Epstein–Barr virus (EBV) is associated with MS, but it is not clear whether EBV plays a role in the pathogenesis of MS. Hypothesis We hypothesized that the immune control of EBV might be defective in MS, and that reactivation of EBV might drive the immune response in MS. Methods We collected blood from controls and patients with MS, and measured the amounts of EBV DNA and RNA using quantitative PCR. Results We found that EBV DNA and RNA were frequently detectable in peripheral blood leukocytes from both patients with MS and normal controls. There was no significant difference between patients with MS or controls. Paired samples from a small number of subjects suggest that EBV DNA may increase before and during clinical relapse. Conclusions We conclude that the immune control of EBV infection is similar in MS and controls, and that reactivation of EBV may correlate with MS disease activity.

Epstein-Barr Virus: Main Pathogenic Agent in Hodgkin Lymphoma Associated Hemophagocytic Syndrome?.

Hemophagocytic syndrome (HPS) is characterized by an uncontrolled proliferation of macrophages displaying extensive phagocytosis of hematopoietic cells that can be associated with non Hodgkin lymphomas. However, Hodgkin lymphoma associated with hemophagocytic syndrome (HL-HPS) has rarely been published. We report here a large series of 34 patients presenting HL-HPS. Histological analysis and Epstein-Barr Virus (EBV) studies were performed. The 34 patients were enrolled from 1992 to 2006. HPS diagnosis was based on usual clinico-biological criteria. Bone marrow aspiration or biopsy were performed in all cases and confirmed HPS, showing hemophagocytic features in scattered macrophages. HL was documented on histological material in all 34 patients. The biopsies were performed on different localizations: lymph nodes (n=18), bone marrow (n=27), liver (n=2) and tonsil (n=1). All histological slides were reviewed and classified according to the World Health Organization (WHO) Lymphoma classification. The presence of EBV in the tumour cells was detected using EBER RNA in situ hybridization and the expression of viral proteins LMP-1, EBNA-2 by immunoperoxidase. Patients were 26 men and 8 women (sex ratio M/F = 3.3). The median age was 45 years (range 19–84). HIV status was negative in 26 patients and positive in 8 patients. All patients were in clinical stage IVB. HL subtypes (18 lymph nodes) were Mixed Cellularity (n=12, 67%), Nodular Sclerosis (n=2, 11%) and Lymphocyte Depleted (n=4, 22%). Extra nodal tissues were highly infiltrated by tumour cells in all cases. The presence of EBV in tumour cells was detected in 32 out of the 34 patients (94%). In all EBV positive cases, high levels of LMP-1 without EBNA2 expression were detected, defining a latency II. This study reports the largest series to date of HL-HPS. The features of HL-HPS are particular by the high proportion of mixed cellularity subtypes (67%) in contrast to the frequency of nodular sclerosis subtypes observed in the general population of non overt immunosuppressed patients, and by the striking high proportion of EBV associated HL (32 out of the 34 patients, 94%). Our findings suggest not only a pathogenic role of EBV, but also a defective immune system in the control of EBV infection in HL-HPS patients.The high predominance of male in our population of HPS-HL (sex ratio M/F = 4.3 after exclusion of HIV positive patients) and the strong association with EBV could suggest X-linked immune defect in these patients.

A Virtual Look at Epstein–Barr Virus Infection: Biological Interpretations

The possibility of using computer simulation and mathematical modeling to gain insight into biological and other complex systems is receiving increased attention. However, it is as yet unclear to what extent these techniques will provide useful biological insights or even what the best approach is. Epstein–Barr virus (EBV) provides a good candidate to address these issues. It persistently infects most humans and is associated with several important diseases. In addition, a detailed biological model has been developed that provides an intricate understanding of EBV infection in the naturally infected human host and accounts for most of the virus' diverse and peculiar properties. We have developed an agent-based computer model/simulation (PathSim, Pathogen Simulation) of this biological model. The simulation is performed on a virtual grid that represents the anatomy of the tonsils of the nasopharyngeal cavity (Waldeyer ring) and the peripheral circulation—the sites of EBV infection and persistence. The simulation is presented via a user friendly visual interface and reproduces quantitative and qualitative aspects of acute and persistent EBV infection. The simulation also had predictive power in validation experiments involving certain aspects of viral infection dynamics. Moreover, it allows us to identify switch points in the infection process that direct the disease course towards the end points of persistence, clearance, or death. Lastly, we were able to identify parameter sets that reproduced aspects of EBV-associated diseases. These investigations indicate that such simulations, combined with laboratory and clinical studies and animal models, will provide a powerful approach to investigating and controlling EBV infection, including the design of targeted anti-viral therapies.

Control of Epstein-Barr virus infection in vitro by T helper cells specific for virion glycoproteins

Epstein-Barr virus (EBV) establishes lifelong persistent infections in humans by latently infecting B cells, with occasional cycles of reactivation, virus production, and reinfection. Protective immunity against EBV is mediated by T cells, but the role of EBV-specific T helper (Th) cells is still poorly defined. Here, we study the Th response to the EBV lytic cycle proteins BLLF1 (gp350/220), BALF4 (gp110), and BZLF1 and show that glycoprotein-specific Th cells recognize EBV-positive cells directly; surprisingly, a much higher percentage of target cells than those expressing lytic cycle proteins were recognized. Antigen is efficiently transferred to bystander B cells by receptor-mediated uptake of released virions, resulting in recognition of target cells incubated with <1 virion/cell. T cell recognition does not require productive infection and occurs early after virus entry before latency is established. Glycoprotein-specific Th cells are cytolytic and inhibit proliferation of lymphoblastoid cell lines (LCL) and the outgrowth of LCL after infection of primary B cells with EBV. These results establish a novel role for glycoprotein-specific Th cells in the control of EBV infection and identify virion proteins as important immune targets. These findings have implications for the treatment of diseases associated with EBV and potentially other coated viruses infecting MHC class II–positive cells.

CD8 T cell recognition of endogenously expressed epstein-barr virus nuclear antigen 1.

The Epstein-Barr virus (EBV) nuclear antigen (EBNA)1 contains a glycine-alanine repeat (GAr) domain that appears to protect the antigen from proteasomal breakdown and, as measured in cytotoxicity assays, from major histocompatibility complex (MHC) class I–restricted presentation to CD8+ T cells. This led to the concept of EBNA1 as an immunologically silent protein that although unique in being expressed in all EBV malignancies, could not be exploited as a CD8 target. Here, using CD8+ T cell clones to native EBNA1 epitopes upstream and downstream of the GAr domain and assaying recognition by interferon γ release, we show that the EBNA1 naturally expressed in EBV-transformed lymphoblastoid cell lines (LCLs) is in fact presented to CD8+ T cells via a proteasome/peptide transporter–dependent pathway. Furthermore, LCL recognition by such CD8+ T cells, although slightly lower than seen with paired lines expressing a GAr-deleted EBNA1 protein, leads to strong and specific inhibition of LCL outgrowth in vitro. Endogenously expressed EBNA1 is therefore accessible to the MHC class I pathway despite GAr-mediated stabilization of the mature protein. We infer that EBNA1-specific CD8+ T cells do play a role in control of EBV infection in vivo and might be exploitable in the control of EBV+ malignancies.

Low-dose immunosuppression reduces the incidence of post-transplant lymphoproliferative disease in pediatric liver graft recipients.

In pediatric solid organ transplantation, the Epstein-Barr virus (EBV)-related lymphoproliferative disorders (PTLD) still play a major role in post-transplant morbidity and mortality. The aim of the study was to determine the incidence of PTLD in pediatric patients with liver transplant who receive low-dose immunosuppression protocols. All pediatric patients (n = 269) received a dual immunosuppression therapy consisting of cyclosporine A (initial trough levels, 170-200 microg/L; trough levels for maintenance immunosuppression after 1 year, 80-100 microg/L) and prednisolone (starting dose, 60 mg/m2). Steroids were reduced to 30 mg/m2 after 1 week, followed by a weekly tapering to 5 mg/m2. Seventy-seven of 269 patients were switched to tacrolimus therapy. The authors evaluated the significance of EBV-DNA monitoring by quantitative polymerase chain reaction in identifying patients at risk for PTLD. Patient survival was 90.3%; graft survival was 85.9%. Eight patients lost their grafts because of chronic rejection. The incidence of PTLD was low (0.7%), although a significant EBV viral load was found in 42.4% of the patients. One third of the patients with a viral load of 3,000 genomes/10(5) cells or greater had clinical signs of EBV infection. The authors conclude that low-dose immunosuppressive protocols significantly reduce the incidence of PTLD. In patients treated with that regimen, the monitoring of EBV viral load seems not to be helpful. It can be assumed that low-dose immunosuppression does not suppress EBV-specific cytotoxic CD8+ T cells, thus allowing the host to control EBV infection without the risk of PTLD. Our low-dose immunosuppression protocol did not increase the risk of chronic rejection.

Low‐Dose Immunosuppression Reduces the Incidence of Post‐transplant Lymphoproliferative Disease in Pediatric Liver Graft Recipients

ABSTRACTObjectivesIn pediatric solid organ transplantation, the Epstein‐Barr virus (EBV)‐related lymphoproliferative disorders (PTLD) still play a major role in post‐transplant morbidity and mortality. The aim of the study was to determine the incidence of PTLD in pediatric patients with liver transplant who receive low‐dose immunosuppression protocols.MethodsAll pediatric patients (n = 269) received a dual immunosuppression therapy consisting of cyclosporine A (initial trough levels, 170–200 μg/L; trough levels for maintenance immunosuppression after 1 year, 80–100 μg/L) and prednisolone (starting dose, 60 mg/m2). Steroids were reduced to 30 mg/m2 after 1 week, followed by a weekly tapering to 5 mg/m2. Seventy‐seven of 269 patients were switched to tacrolimus therapy. The authors evaluated the significance of EBV‐DNA monitoring by quantitative polymerase chain reaction in identifying patients at risk for PTLD.ResultsPatient survival was 90.3%; graft survival was 85.9%. Eight patients lost their grafts because of chronic rejection. The incidence of PTLD was low (0.7%), although a significant EBV viral load was found in 42.4% of the patients. One third of the patients with a viral load of 3,000 genomes/105 cells or greater had clinical signs of EBV infection.ConclusionsThe authors conclude that low‐dose immunosuppressive protocols significantly reduce the incidence of PTLD. In patients treated with that regimen, the monitoring of EBV viral load seems not to be helpful. It can be assumed that low‐dose immunosuppression does not suppress EBV‐specific cytotoxic CD8+ T cells, thus allowing the host to control EBV infection without the risk of PTLD. Our low‐dose immunosuppression protocol did not increase the risk of chronic rejection.

Epstein–Barr virus nuclear antigen 1 (EBNA1) induced cytotoxicity in epithelial cells is associated with EBNA1 degradation and processing

Epstein–Barr virus nuclear antigen 1 (EBNA1) has a central role in the maintenance and segregation of the Epstein–Barr virus (EBV) episome and by virtue of a glycine–alanine repeat domain is prevented from being endogenously processed for recognition by HLA class I restricted cytotoxic T lymphocytes (CTLs). We found that EBNA1 expression resulted in growth inhibition and a G2/M arrest in human squamous epithelial cell lines (SCC12F, SVK) but not epithelial cell lines of glandular origin (Hela, Ad/AH). The cytotoxicity of EBNA1 was associated with EBNA1 degradation and both these effects were blocked in SCC12F cells expressing either the anti-apoptotic bcl-2 protein or the EBV homolog of bcl-2, BHRF1. The endogenous degradation of EBNA1 in SVK epithelial cells was associated with specific CTL recognition, an effect not evident in EBNA1-expressing Hela cells. Consistent with the inability of SVK cells to tolerate EBNA1 expression, studies with a recombinant EBV demonstrated that SVK cells are unable to maintain stable virus infection, whereas Hela cells are able to efficiently establish latent EBV infection. These data have important implications for both the cellular requirements necessary to sustain a stable EBV infection and for the possible role of CTL responses in controlling EBV infection of epithelial cells.

Antiviral treatment of Epstein-Barr virus-associated lymphoproliferations.

Epstein-Barr virus (EBV)-associated lymphoproliferations may arise in individuals with hereditary or acquired immunodeficiencies. T-cell dysfunction and resulting insufficient control of EBV infection is common to all these patients in whom EBV-associated lymphoproliferations develop. EBV is an oncogenic virus which induces proliferation and transformation of B-lymphocytes. Antiviral treatment may represent a causal treatment option with relatively low toxicity. Among the different antiviral drugs aciclovir and ganciclovir are not the drugs of choice, because in EBV-associated lymphoproliferations the viral thymidine kinase enzyme is not encoded regularly. The agent arginine butyrate has the ability to selectively activate EBV thymidine kinase genes in EBV-infected lymphoma cells. In combination with ganciclovir it has demonstrated efficacy in patients with EBV-associated lymphoproliferations after solid organ transplantation. The action of foscarnet, another antiviral agent, is directed against the viral DNA, independent of the presence of the viral thymidine kinase. In our experience treatment with foscarnet resulted in continuous complete remissions in patients with EBV-associated lymphoproliferations. These clinical experiences demonstrate the efficacy of antiviral treatment in EBV-associated lymphoproliferations.

Redox control of EBV infection: prevention by thiol-dependent modulation of functional CD21/EBV receptor expression.

CD21 serves as a receptor for the Epstein-Barr virus (EBV). In this report, surface expression of CD21 on B and T cells was shown to be suppressed by a thiol-antioxidant, N-acetylcysteine (NAC), in a dose- and time-dependent manner. In contrast, expression of other surface markers, CD25 and CD4 for T cells and CD19 and surface IgM for B cells, was not affected by NAC. When an EBV-negative B-cell line B104 was treated with NAC, the cells were not susceptible to infection with B95-8-derived EBV. The effect of NAC was shown to be irrelevant to the transcriptional levels of CD21 mRNA and the intracellular glutathione levels. Immunoprecipitation study revealed that NAC causes a loss of anti-CD21 monoclonal antibody (HB5) binding to both membrane and soluble CD21, suggesting that NAC modulates the structure of CD21. Other thiol-antioxidants, such as 2-mercaptoethanol, pyrrolidine dithiocarbamate, and glutathione, showed similar effect to NAC on CD21 expression. These results suggest the possible modulation of EBV infection via thiol-dependent redox control of CD21, and thiol-antioxidants may be good candidates for controlling EBV infection.

Role of LMP1 in immune control of EBV infection

The Epstein–Barr virus (EBV) encoded latent membrane protein (LMP1) plays a crucial role in the long-term persistence of this virus within the cells of the immune system. Not only is this protein critical for the transformation of resting B cells by EBV, it also displays pleiotropic effects on various cellular proteins expressed in the host cell. These include up-regulation of expression of B cell activation antigens, adhesion molecules and various components of the antigen processing pathway. Here we discuss how LMP1 acts like an expression ‘switch’ which, depending on the stage of EBV infection, manoeuvres various pathways that either modulate the immune system towards or against its survival.

Strategies Involved in Developing an Effective Vaccine for EBV-Associated Diseases

Publisher Summary This chapter first considers EBV host–virus relationships and then proceeds to discuss the immune control of EBV infection. Epstein–Barr virus (EBV) is encoded by a linear, double-stranded DNA genome of 172 kb that includes almost 100 identified open reading frames. The virus maintains a lifelong latent association with B lymphocytes and a permissive association with stratified epithelium in the oropharynx. Two major subtypes of EBV have been identified, A type and B type (also known as EBV-1 and EBV-2). It is possible to characterize three distinct forms of EBV latency (latency I, latency II, and latency III) that are distinguished on the basis of expression of EBV latent genes and promoter usage. These latency patterns or programs form a convenient means of classifying EBV-associated diseases and are the basis for vaccine development. The humoral response to EBV infection is defined in terms of a set of immunofluorescence assays that quantitatively assessed the antibody response to virus capsid antigen (VCA), membrane antigen (MA), early antigen-restricted (EA-R), early antigen-diffuse (EA-D), and EBV-induced nuclear antigens (EBNA). Significantly increased shedding of EBV in the oropharynx of immunosuppressed individuals provides evidence in support of an important role for T cells in controlling EBV infection. It is unlikely that a single vaccine that is applicable to all EBV-associated diseases will be developed in the near future. Given the variety of potential EBV targets in latency III diseases and the problems of immune recognition of latency II and latency I diseases, vaccines against infectious mononucleosis (IM) and posttransplantation lymphoproliferative disorders (PTLD) would seem to offer the best opportunity for early development. Vaccine trials against other EBV-associated diseases may need to proceed with more caution and may be dependent on the emergence of novel vaccine strategies derived from either animal models or related viruses.

Immune regulation in Epstein-Barr virus-associated diseases.

Epstein-Barr virus (EBV) is a member of the human herpesvirus family and, like many other herpesviruses, maintains a lifelong latent association with B lymphocytes and a permissive association with stratified epithelium in the oropharynx. Clinical manifestations of primary EBV infection range from acute infectious mononucleosis to an asymptomatic persistent infection. EBV is also associated with a number of malignancies in humans. This review discusses features of the biology of the virus, both in cell culture systems and in the natural host, before turning to the role of the immune system in controlling EBV infection in healthy individuals and in individuals with EBV-associated diseases. Cytotoxic T cells that recognize virally determined epitopes on infected cells make up the major effector arm and control the persistent infection. In contrast, the options for immune control of EBV-associated malignancies are more restricted. Not only is antigen expression restricted to a single nuclear antigen, EBNA1, but also these tumor cells are unable to process EBV latent antigens, presumably because of a transcriptional defect in antigen-processing genes (such as TAP1 and TAP2). The likelihood of producing a vaccine capable of controlling the acute viral infection and EBV-associated malignancies is also discussed.

Elevated antibody titers to Epstein-Barr virus prior to the diagnosis of Epstein-Barr-virus-associated gastric adenocarcinoma.

Epstein-Barr virus (EBV) has recently been identified in the tumor cells of patients with gastric carcinoma. We tested pre-morbid serum samples from a carefully monitored cohort of Japanese men in order to investigate the possibility that patients with EBV-associated gastric cancer represent a sub-set of individuals with long-standing difficulties in appropriately managing EBV infection. From a serum bank, we obtained 108 samples derived from 54 patients destined to develop gastric adenocarcinoma and 54 controls. Samples were tested under code for antibodies to EBV-capsid antigen, early antigen and nuclear antigen. Individuals who were positive for IgA antibodies against EBV viral-capsid antigen (VCA) and IgG antibodies against the R component of EBV early antigen were at a 3.9-fold and 1.9-fold excess risk of disease, respectively. Antibody titers to EBV VCA were significantly higher in those destined to get EBV-associated gastric cancer than those subsequently developing non-EBV-associated gastric cancer or age-and-gender-matched controls. These findings suggest that the inability to control EBV infection on a long-term basis exists many years prior to the development of EBV-associated gastric cancer, and that EBV may play an etiologic role in this sub-set of malignancies.

Immune regulation in Epstein-Barr virus-associated diseases.

Epstein-Barr virus (EBV) is a member of the human herpesvirus family and, like many other herpesviruses, maintains a lifelong latent association with B lymphocytes and a permissive association with stratified epithelium in the oropharynx. Clinical manifestations of primary EBV infection range from acute infectious mononucleosis to an asymptomatic persistent infection. EBV is also associated with a number of malignancies in humans. This review discusses features of the biology of the virus, both in cell culture systems and in the natural host, before turning to the role of the immune system in controlling EBV infection in healthy individuals and in individuals with EBV-associated diseases. Cytotoxic T cells that recognize virally determined epitopes on infected cells make up the major effector arm and control the persistent infection. In contrast, the options for immune control of EBV-associated malignancies are more restricted. Not only is antigen expression restricted to a single nuclear antigen, EBNA1, but also these tumor cells are unable to process EBV latent antigens, presumably because of a transcriptional defect in antigen-processing genes (such as TAP1 and TAP2). The likelihood of producing a vaccine capable of controlling the acute viral infection and EBV-associated malignancies is also discussed.

Low-dose interleukin 2 prevents the development of Epstein-Barr virus (EBV)-associated lymphoproliferative disease in scid/scid mice reconstituted i.p. with EBV-seropositive human peripheral blood lymphocytes.

When severe combined immune deficient (SCID) mice undergo i.p. injection with peripheral blood lymphocytes from normal human donors seropositive for EBV, a majority of these mice (hu-PBL-SCID mouse model) subsequently develop a fatal EBV+ lymphoproliferative disease (EBV-LPD) of human B-cell origin. Because T cells normally are critical in the control of EBV infection, we hypothesized that human T-cell dysfunction accounts for EBV-LPD in the hu-PBL-SCID mouse and that systemic administration of T-cell-derived cytokines would reestablish protective immunity against EBV-LPD. We show that the daily s.c. administration of a very low dose (500 international units) of polyethylene glycol-modified recombinant human interleukin 2 (PEG-IL-2) to hu-PBL-SCID mice can prevent the development of fatal EBV-LPD and significantly improves survival (78%), compared with the survival of hu-PBL-SCID mice treated with placebo (20%, P = 0.0008). Additional lymphocyte-depletion experiments showed that mouse natural killer cells and human CD8+ T cells provided cellular immunity necessary for the PEG-IL-2-mediated protective effect, whereas i.p. injection of human peripheral blood lymphocytes depleted of CD4+ T cells had no adverse effect when combined with PEG-IL-2 therapy and may have been beneficial. These data establish that very low-dose PEG-IL-2 therapy can overcome the immune deficiencies that lead to EBV-LPD in the hu-PBL-SCID mouse and point to the usefulness of this model for evaluating cytokine therapies in EBV-LPD. The use of low-dose IL-2 as a preventative immune therapy has potential application in immunocompromised individuals at high risk for EBV-LPD.

The interleukin-10 homolog encoded by Eepstein-Barr virus enhances the reactivation of virus-specific cytotoxic T cell and HLA-unrestricted killer cell responses

We determined what influence the Epstein-Barr virus (EBV)-encoded homologue of IL-10 (viral or vIL-10) had on immune responses important for the control of EBV infection. We produced recombinant vIL-10 in a B cell line. A 17-kDa recombinant protein was secreted and had the same molecular weight as vIL-10 secreted by EBV-infected B cells. Functional activity of recombinant vIL-10 was shown by the inhibition of interferon-γ production by activated leukocytes. Cytotoxic T cells and HLA-unrestricted activated killer cells are both important arms of the immune response to EBV. vIL-10, either expressed by B cell stimulators or added exogenously, enhanced the in vitro reactivation of allo- and EBV-specific cytotoxic T cells. vIL-10 also enhanced the activation of HLA-unrestricted killer cells by EBV-transformed B cells. In contrast, the interleukin-2-mediated activation of these killers was unaffected. Since vIL-10 is expressed during the lytic cycle of EBV, we conclude that the expression of vIL-10 may enhance immune responses to EBV-infected cells during periods of virus replication in vivo. In this way, the virus may limit its own replication and maintain the apathogenic virus carrier state that is characteristic of EBV.

Epstein-Barr Virus-Associated Lymphoproliferative Disorders in Immunocompromised Individuals

Publisher Summary The Epstein–Barr virus (EBV) acts as one of a number of factors including environmental and genetic elements that contribute to the pathogenesis of Burkitt's lymphoma (BL). Apart from BL, EBV is associated with a wide spectrum of lymphoproliferative diseases that develop in a setting of inherited or acquired immunodeficiency. A common factor in the development of these lesions is thought to be an underlying deficit in the normal immunoregulatory mechanisms that control EBV infection in vivo. Through major advances in the field of molecular biology, progress has been made in elucidating the structure and function of the EBV genome, thereby providing important insights into the oncogenic role of EBV in human neoplasia. There is also increasing awareness that EBV may be causally linked to a wide range of lymphoproliferative disorders in which impairment of EBV-specific host immunity appears to be an important underlying factor. In many instances, EBV-related lymphoproliferative disorders in immune-compromised individuals fulfill established criteria for malignancy based on histology, evidence of clonality, and rapidly aggressive clinical course. However, a proportion of these tumors developing in the context of iatrogenic immune suppression for organ and bone marrow transplantations undergoes complete resolution following the withdrawal of immunosuppressive therapy, either alone or in combination with antiviral agents. The consensus is that the clinical, morphological, cytogenetic, and clonal heterogeneities of these tumors reflect a spectrum of changes through which a polymorphic, polyclonal hyperplastic process induced by EBV evolves to an oligoclonal and ultimately multiclonal or monoclonal malignant tumor population.