SEARCH

SEARCH BY CITATION

Keywords:

  • virus;
  • lymphoma;
  • leukaemia;
  • EBV;
  • HTLV-1;
  • HHV-8;
  • HCV;
  • SV40

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Human T-cell leukaemia virus type 1
  5. Epstein–Barr virus
  6. Human herpesvirus 8
  7. Human immunodeficiency virus
  8. Hepatitis C virus
  9. SV40
  10. Conclusions
  11. Acknowledgements
  12. References

Viruses of the retrovirus and herpesvirus families are aetiological agents of human leukaemias and lymphomas. The human T-cell leukaemia virus type 1 causes adult T-cell leukaemia and the Epstein–Barr virus is associated with Burkitt's lymphoma, lymphomas in immunosuppressed people, and Hodgkin lymphoma. The discovery of human herpesvirus type 8 has led to the identification of a rare and unusual group of virus-associated lymphoproliferative diseases. Individuals infected with the human immunodeficiency virus are at greatly increased risk of developing lymphoma but here the mechanism of lymphomagenesis is indirect. Recent data suggest that hepatitis C virus infection is also associated with an increased incidence of lymphoma, whereas data relating to SV40 remain controversial. Copyright © 2006 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Human T-cell leukaemia virus type 1
  5. Epstein–Barr virus
  6. Human herpesvirus 8
  7. Human immunodeficiency virus
  8. Hepatitis C virus
  9. SV40
  10. Conclusions
  11. Acknowledgements
  12. References

Viruses are aetiologically associated with a significant minority of human leukaemia/lymphomas. Recognition of virus involvement in these malignancies is important as prevention of infection can lead to a reduction in the number of individuals at risk of disease. Furthermore, specific anti-viral therapies, including immunotherapy, can be developed for use in patient management. This review focuses on the biology of human T-cell leukaemia virus type 1 (HTLV-1) and Epstein–Barr virus (EBV) and the mechanisms involved in lymphomagenesis. Human herpesvirus 8 (HHV-8) is mentioned only briefly, as this virus is described in greater detail elsewhere in this issue. A brief overview of the lymphomas occurring in the context of human immunodeficiency virus (HIV) infection is presented and data suggesting that hepatitis C virus (HCV) and simian virus 40 (SV40) are associated with lymphoma are discussed. The basic features of virus-associated lymphomas are summarized with an emphasis on recent data; for more detailed information on the many facets of this subject, the reader is referred to previous excellent reviews.

Human T-cell leukaemia virus type 1

  1. Top of page
  2. Abstract
  3. Introduction
  4. Human T-cell leukaemia virus type 1
  5. Epstein–Barr virus
  6. Human herpesvirus 8
  7. Human immunodeficiency virus
  8. Hepatitis C virus
  9. SV40
  10. Conclusions
  11. Acknowledgements
  12. References

HTLV-1 is a member of the deltaretrovirus genus of the retrovirus family, which includes the bovine leukaemia virus as well as the primate T-cell leukaemia viruses 1. HTLV-1 infection is endemic in Japan, the Caribbean basin, central Africa, parts of South America, Melanesia, Papua New Guinea, and the Solomon Islands 2, 3. It is estimated that there are 15–20 million carriers of the virus worldwide 2. HTLV-2 is a related retrovirus, with 65–70% genomic sequence identity, which is endemic in Amerindian tribes and pygmies 4, 5. In other parts of the world, HTLV-1 is mainly detected in immigrants from endemic areas, although HTLV-1 and particularly HTLV-2 are found in intravenous drug abusers 2. HTLV-1 is thought to have arisen as a result of multiple interspecies transmissions from simians to humans, whereas HTLV-2 viruses appear to have originated from a common ancestor resulting from a single simian to human transmission 4. Recently, viral sequences from a further two human viruses have been identified in Africa and designated HTLV-3 and HTLV-4; HTLV-3 is closely related to STLV-3, whereas no simian counterpart of HTLV-4 has been identified as yet 6, 7.

HTLV-1 is the causative agent of adult T-cell leukaemia (ATL) and the progressive myelopathy HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) 2, 8. The geographical distribution of these diseases follows the distribution of the virus. ATL is an aggressive malignancy of mature CD4+ T-cells, which is characterized by ATL cells with typical morphology, frequent cutaneous involvement, hypercalcaemia and lytic bone lesions, parenchymal infiltration, and immune dysfunction 2, 8. Most patients die within 1 or 2 years of diagnosis, usually of infections or hypercalcaemia 9. Smouldering ATL and chronic ATL are also described but these forms generally progress to acute ATL. In lymphoma-type ATL, there is marked lymphadenopathy without overt leukaemia 2. The lifetime risk of developing ATL among HTLV-1 carriers in Japan is 6.6% for men and 2.1% for women 10, with young age at infection being associated with an increased risk of leukaemia 11.

HTLV-1 is a highly cell-associated virus and efficient transmission requires transfer of infected cells and cell-to-cell contact 9, 12. The major route of transmission is via infected cells in breast milk but transmission through infected blood products and sexual transmission also occur 9. HTLV infection is usually diagnosed using a screening enzyme-linked immunosorbent assay or particle agglutination assay followed by confirmatory immunoblotting 2. However, the most sensitive and specific way to detect viral infection is to use PCR assays detecting several regions of the viral genome 13.

Following infection of a cell with HTLV-1, the RNA genome is transcribed into DNA and integrates into host cell chromosomal DNA 1. Infection of that cell is therefore life-long and the viral genome is passed on to daughter cells. Mitotic division of infected cells appears to be the major route of expansion of HTLV-1 since transmission of the virus is inefficient. The major mechanism involved in the leukaemogenic process is transactivation (see below) and not insertional activation or oncogene transduction as seen in animal leukaemias caused by retroviruses. Like other retroviruses, the genome consists of gag, pol, and env genes, which encode important structural and functional proteins, flanked by long terminal redundancies (LTRs), which contain sequences important for viral transcription and replication 1. In addition, there is a region at the 3′ end of the genome which encodes a number of accessory proteins that play important roles in the transformation process; these include Tax, Rex, p12, p13, p30, and HBZ 2, 14.

Tax is a multifunctional protein which, in experimental systems, is both necessary and sufficient for transformation by HTLV-1 2, 15, 16. It interacts with transcription factors and molecules involved in signal transduction pathways, leading to dysregulation of both viral and cellular genes 17. Up-regulation of transcription by Tax, or transactivation, largely occurs through interaction with the CREB/ATF, NF-κB, and SRF/AP-1 pathways 17. NF-κB activation is a feature of HTLV-1-infected and ATL cells and is thought to play a critical role in the transformation process 18. NF-κB activation occurs through two pathways; the classical pathway is important for adaptive immune responses and inflammation, whereas the alternative pathway regulates B-cell maturation and lymphoid organogenesis. By functioning as an adaptor molecule, or molecular bridge, Tax activates both of these pathways 18. NF-κB activation leads to increased expression of many cytokines and their receptors, including IL2 and the IL2-Rα, which leads to polyclonal proliferation of HTLV-1-infected cells by autocrine and paracrine mechanisms 13, 19, 20. In addition, NF-κB stimulation causes increased expression of proteins with anti-apoptotic function including Bcl-xL and survivin 21, 22.

Many of the cellular genes dysregulated by Tax are involved in cell cycle control, apoptosis, and DNA repair 23. Tax expression leads to potent activation of cyclin D and CDKs 4 and 6, leading to G1 progression and S-phase entry 24–26. Functional inactivation of p53 by Tax subverts DNA-damaged induced G1 arrest, and inhibition of the INK4 family of CDK inhibitory proteins, through two independent mechanisms, leads to loss of checkpoint control 23, 27. DNA repair is also compromised by Tax; transcriptional down-regulation of DNA polymerase β leads to decreased base excision repair and activation of PCNA is associated with inhibition of nucleotide excision repair 28, 29. Binding of Tax to the anaphase-promoting complex leads to premature activation of this complex and loss of key cell-cycle regulators; although this leads to slower progression through G2/M, it is also the most likely cause of mitotic aberrations in infected cells 30. Tax expression also leads to up-regulation of TGF-β, but HTLV-1-infected cells are resistant to TGF-β-induced growth suppression 31.

Additional functions are contributed by other accessory proteins. Rex regulates the intracellular transport of unspliced and singly spliced HTLV-1 transcripts 2; although essential for viral replication, Rex is dispensable for transformation 32. p12 is a small, multifunctional protein, which may contribute to viral pathogenesis by causing NFAT activation, STAT5 activation through binding the IL-2R β chain, and down-regulation of surface HLA class I 9, 33. Excess Tax appears harmful, and Rex, p30, and HBZ all play roles in suppressing Tax expression 9, 14.

Provirus load in carriers of the virus varies 1000-fold between individuals but appears to remain stable over time 34. Recent data suggest that a high provirus load increases the risk of both transmission to an uninfected person and developing ATL 9, 35. Infected persons mount vigorous humoral and cell-mediated immune responses to HTLV-1 but the major determinant of provirus load appears to be the cytotoxic T lymphocyte (CTL) response 36. HTLV-1-specific CTLs recognizing both structural and accessory proteins have been detected but the dominant response is to Tax 36. Comparisons of ATL and HAM/TSP patients suggest that the magnitude of the CTL response is reduced in ATL patients but longitudinal studies are required to determine whether this is cause or effect 37.

The ability of HTLV-1 to stimulate T-cell proliferation and the multiple transforming properties of Tax suggest a clear mechanism by which the virus causes T-cell leukaemia. However, there is a paradox. In the majority of ATL cases, there is no evidence of expression of Tax 9. This results from mutation or deletion of tax or LTR sequences and epigenetic silencing of the 5′ LTR 9. The current model of ATL pathogenesis is therefore one in which initial infection by HTLV-1 leads to Tax expression and polyclonal expansion of infected CD4+ cells. At this stage, proliferation is controlled by the CTL response. Over time, proliferation and Tax expression lead to genetic and epigenetic changes in the host genome and to the outgrowth of a leukaemic clone that no longer expresses Tax.

HTLV-2 has been associated with HAM/TSP and various chronic inflammatory conditions 13. Although the virus was originally isolated from a patient with a T-cell variant of hairy cell leukaemia, there is no definitive evidence that HTLV-2 causes lymphoproliferative disease 2.

Epstein–Barr virus

  1. Top of page
  2. Abstract
  3. Introduction
  4. Human T-cell leukaemia virus type 1
  5. Epstein–Barr virus
  6. Human herpesvirus 8
  7. Human immunodeficiency virus
  8. Hepatitis C virus
  9. SV40
  10. Conclusions
  11. Acknowledgements
  12. References

EBV is a γ herpesvirus with a worldwide distribution 38. The vast majority (>90%) of healthy adults are persistently infected by this virus with a reservoir of infection in memory B-cells 38, 39. In developing countries, infection usually occurs in early childhood, whereas in industrialized countries primary infection is often delayed until adolescence. Infection in childhood usually goes unnoticed, whereas delayed infection frequently results in infectious mononucleosis (IM) 38. The virus is shed in saliva and this is the major vehicle for spread of the virus, although transmission by other routes, such as blood transfusion and transplantation, also occurs and is clinically important 38, 40.

EBV is associated with both benign and malignant diseases, the latter including lymphomas and carcinomas. The three most important EBV-associated lymphomas are Burkitt's lymphoma (BL), Hodgkin lymphoma (HL), and lymphomas occurring in the context of immunosuppression 38. In addition, the virus is associated with several rarer entities including primary effusion lymphoma (PEL), pyothorax-associated lymphoma, and T/NK cell lymphomas. Since EBV is a ubiquitous virus, the geographical distribution of EBV-associated diseases is not related to the distribution of the virus, but relates to the distribution of co-factors and the presence of immunosuppression.

The genome of EBV is ∼184 kilobases 41, about 20 times the size of the HTLV-1 genome. Within the infected cell, the genome is maintained extrachromosomally in the nucleus in a circular form and integration is infrequent 41. Lytic cycle infection is associated with production of viral particles and death of the infected cell. In contrast, during latent infection, which is associated with transformation by EBV, only a restricted group of viral antigens is expressed 41, 42. These include six EBV nuclear antigens (EBNAs 1, 2, 3A, 3B, 3C, and -LP), and three latent membrane proteins (LMPs 1, 2A, and 2B). Two non-coding RNA transcripts, the EBERs, are also expressed at very high levels in the nuclei of all latently infected cells. Transcripts from the BamHIA region of the virus (BARTS) are expressed but are less well characterized 42. EBV is an extremely efficient transforming agent and EBV infection of B-cells in vitro leads to immortalization of these cells and establishment of permanent lymphoblastoid cell lines (LCLs).

EBNA2 and LMP1 expression are essential for immortalization of B-cells by EBV in vitro and EBNA1, EBNA3A, EBNA3C, and EBNA-LP also play key roles 42. EBNA1 is required for the maintenance and replication of the episomal EBV genome and also plays a role in transcriptional regulation 41, 42. The ability of EBNA1 to contribute directly to transformation is controversial 43, 44, but recent in vitro studies suggest that this protein plays a role in prevention of apoptosis 45. Like the Tax protein of HTLV-1, EBNA2 is a transcriptional transactivator which regulates the expression of both viral and cellular genes 41, 42. EBNA2 activates transcription by binding to the transcriptional repressor RBP-J and this leads to up-regulation of several proteins including LMP1, 2A, and the cellular CD23 antigen. The EBNA2 RBP-J interaction mimics activation of signalling through Notch receptors 46. Transcriptional activation of EBNA2 is regulated by the EBNA3 proteins, which can also bind RBP-J and inhibit transactivation by EBNA2; this situation is reminiscent of Tax repression by other HTLV-1 accessory proteins. In addition, EBNA3C interacts with proteins involved in cell cycle regulation and progression 42.

LMP1 mimics a constitutively activated CD40 molecule and expression leads to ligand-independent signalling through NF-κB, AP1, and JAK-STAT pathways 47–49. Both classical and alternative NF-κB pathways are activated by LMP1 inducing up-regulation of cytokines, chemokines, and anti-apoptotic proteins 42. LMP2A is also a multifunctional protein; by binding to tyrosine kinases, LMP2 can both inhibit signalling through the B-cell receptor (BCR) and deliver a B-cell survival signal that substitutes for BCR signalling and leads to rescue of BCR-deficient B-cells in transgenic mouse models 50. In addition, expression of LMP2A results in changes in the expression pattern of many B-cell genes and inhibition of signalling from TGF-β 51, 52. Expression of the EBER RNAs is not essential for transformation of B-cells but these transcripts play a role in cell survival and protection from the anti-viral effects of interferons 42.

Transformation of B-cells in vitro is associated with expression of the full spectrum of latent genes mentioned above; this pattern of gene expression is referred to as latency III or the growth programme 38, 39. More restricted patterns of EBV latent gene expression were originally described in B-cells in vitro, but are also observed in malignancies associated with EBV. In type I latency, EBNA1 is the only latent antigen expressed, whereas in latency II, the EBNA1 and LMP proteins are expressed but the remaining EBNAs are down-regulated. EBER RNAs are expressed in all forms of latent infection.

Although EBV is an extremely efficient transforming agent and infection is almost universal in adults, few individuals develop EBV-associated lymphomas. This is because EBV elicits strong immune responses, particularly CTL responses; it has been estimated that EBV-specific T-cells might constitute up to 5% of circulating CD8+ T-cells 38, 53. Among the latent antigens, the EBNA3 proteins are immunodominant, although T-cells reactive with LMP2, LMP1, and EBNA1 are detectable in healthy individuals 38, 54. In view of the critical role of CTLs in controlling EBV infection, it is not surprising that EBV-driven lymphoproliferations occur in individuals who are immunocompromised. It is likely that most EBV-associated lymphomas are associated with some degree of host : virus imbalance, since increased viral loads are associated with BL and EBV-associated HL in addition to lymphomas in the immunosuppressed 55. Down-regulation of latent viral antigens and, in the case of BL, HLA class I antigen processing also contribute to immune evasion 38.

Unlike the situation with HTLV-1, demonstration of EBV seropositivity is not useful when investigating EBV involvement in lymphoma. It is essential to demonstrate the presence of the virus within the malignant cells before categorizing a tumour as EBV-associated. This is best done by EBER in situ hybridization since the EBER transcripts are extremely abundant, relatively stable, and expressed in all forms of viral latency (Figure 1). LMP1 immunohistochemistry (Figure 1), particularly when combined with antigen retrieval, is also a useful and sensitive assay but LMP1 is not expressed in all forms of latency and LMP1 staining must not be regarded as synonymous with EBV immunohistochemistry. EBNA2 antibodies, which work well on fixed sections, are commercially available and expression of EBNA2 is usually considered indicative of a latency III pattern of gene expression.

thumbnail image

Figure 1. Detection of EBV in the Hodgkin and Reed–Sternberg cells of classical Hodgkin lymphoma. (a) EBER in situ hybridisation; (b) LMP1 immunohistochemistry

Download figure to PowerPoint

Burkitt's lymphoma

EBV was first identified in cell cultures from a case of African BL. The virus was subsequently shown to be associated with all cases of endemic BL (eBL), a childhood tumour that occurs in equatorial Africa and Papua New Guinea in areas with perennial and intense exposure to malaria (holoendemic malaria) 38. BL also occurs at lower incidence in other geographical areas (sporadic BL) but only 15–25% of these cases are EBV-associated. Although malaria is a recognized co-factor in the development of eBL, the precise role of malarial infection in disease pathogenesis is not clear, although B-cell stimulation and T-cell immunosuppression are likely to be involved. eBL patients have elevated titres of EBV antibodies, which precede the development of disease, and increased numbers of circulating EBV-infected cells. A recent study found that EBV viral load was higher in young children from an area of Africa with holoendemic malaria than in children from an area with sporadic infection, suggesting that malarial infection modulates persistent EBV infection 56.

BL cells are characterized by chromosomal translocations involving the c-myc gene on chromosome 8 and one of the immunoglobulin (Ig) gene loci on chromosomes 14, 2 or 22 38. These translocations lead to dysregulation of c-myc and enhanced cellular proliferation. Overexpression of c-myc also leads to enhanced apoptosis and so tumours associated with myc dysregulation usually harbour further mutations which result in inhibition of apoptosis 57. In BL, EBNA1 is the only viral antigen that is consistently expressed and this has led to speculation about whether the virus plays any role in the maintenance of the malignant phenotype. However, recent data showing that EBNA1 expression contributes to cell survival suggest that this viral protein may counteract the apoptotic effects of c-myc in eBL 45.

The tumour cells in BL have a germinal centre phenotype, consistently expressing CD10, CD38, CD77, and the recently identified HGAL protein 38, 58. However, sequence analysis of Ig genes in primary BL material does not show evidence of ongoing somatic hypermutation, suggesting that the tumour cell is in fact a late germinal centre B-cell or memory cell 59. It is therefore likely that the germinal centre phenotype of BL cells reflects the c-myc dysregulation rather than the origin of the tumour cell. Analysis of the pattern of somatic hypermutation in EBV-positive BL, as distinct from EBV-negative BL, also suggests that antigen selection has occurred in these cells 59.

Hodgkin lymphoma

HL presents both an unusual histological picture and intriguing epidemiology 60. In industrialized countries, there is a bimodal incidence, with the first peak occurring in the age range 15–34 years (young adult peak) and the second peak occurring at ≥50 years of age (older adult peak). Developed countries are classically described as showing a first incidence peak in childhood, the absence of a young adult peak, and a second peak in the older adult age range. In practice, many variations on these themes exist 61. Risk factors suggest that delayed exposure to a common infectious agent plays a role in the pathogenesis of young adult HL 62.

Although studies performed in the 1970s showed that HL patients had increased EBV antibody titres and were significantly more likely to have had previous IM than controls, it was not until the mid-1980s that there was any molecular evidence for an association between HL and EBV 60, 63. In 1987, Weiss et al published a report describing the detection of clonal EBV genomes in HL biopsies by Southern blot analysis 64. A flurry of studies reporting similar results soon followed and these, in turn, were followed by studies localizing the viral sequences to Hodgkin and Reed–Sternberg (HRS) cells, the tumour cells in HL 60, 65. The virus is associated with cases of classical HL and not with nodular lymphocyte predominant HL; within classical HL, cases of the mixed cellularity subtype are more likely to be EBV-associated than nodular sclerosis cases 65. Contrary to expectation, EBV is not associated with the young adult age-specific incidence peak, but is more frequently associated with childhood and older adult cases 65. On the basis of presence of EBV in HRS cells, age at diagnosis, and previous IM, we have proposed a four-disease model of classical HL (Figure 2) 63.

thumbnail image

Figure 2. Four-disease model of classical Hodgkin lymphoma. The model divides classical Hodgkin lymphoma (cHL) into four subgroups on the basis of age at diagnosis, EBV association, and history of infectious mononucleosis. Three subgroups of EBV-associated cases are recognized: 1—a childhood group including almost all cases occurring under the age of 10 years; 2—a young adult group, which is associated with previous infectious mononucleosis; and 3—an older adult group which we speculate is associated with an imbalance in the normal host : virus equilibrium. Although the older adult cases typify the latter subgroup, all cHL cases with evidence of immunosuppression fall into this category. 4—Superimposed on these is a single group of EBV-negative cases that accounts for the young adult age-specific incidence peak. The overall shape of the age-specific incidence curve in any particular geographical locale will reflect the relative contributions of each of these four disease subgroups

Download figure to PowerPoint

HRS cells make up only a small proportion, usually less than 1%, of the cells within HLs. The scarcity and fragility of these cells, their lack of lineage markers, and the lack of model systems hindered research into the origin of HRS cells and it was not until the advent of single cell molecular techniques that this issue was resolved. There is now compelling evidence that HRS cells in classical HL are derived from pre-apoptotic germinal centre B-cells 66. HRS cells have clonal Ig gene rearrangements that show evidence of somatic hypermutation but lack intraclonal diversity indicating that somatic hypermutation has ceased. In a significant proportion of cases, there is evidence that the somatic hypermutation process has introduced crippling mutations into the rearranged Ig genes 66. Surface Ig, and therefore BCR complexes, is not expressed and it is not clear how these cells are able to escape apoptosis, the normal fate of B-cells lacking BCRs. Recent data from three laboratories have shown that EBV infection in vitro can rescue BCR-deficient germinal centre B-cells and drive them into proliferation 67–69, suggesting a critical role for EBV in this process.

EBV-positive HRS cells express EBNA1, LMP1, LMP2A, LMP2B, and the EBER RNAs, but consistently lack EBNA2 (latency II) 63, 65. LMP1 is likely to contribute to survival and proliferation of HRS cells through activation of NF-κB and AP-1 47, 70. The role of LMP2A is more difficult to predict. Although LMP2A can deliver a survival signal in B-cells, HRS cells have down-regulated many B-cell-specific molecules including intracellular components involved in this signaling pathway 70, 71. LMP2A may indeed contribute to this ‘loss of B-cell signature’, since cDNA microarray analysis of LMP2A-expressing B-cells reveals a similar pattern of down-regulated genes 51. It is also possible that EBNA1 and the EBERs contribute to the rescue of HRS cells from apoptosis 42, 45.

Lymphomas in immunosuppressed individuals

Given the importance of CTLs in the control of EBV infection, it is not surprising that EBV-associated lymphomas arise in individuals with compromised T-cell responses. Lymphoproliferative diseases associated with EBV occur in individuals with primary, acquired, and iatrogenic immunosuppression. The best studied of these are the EBV-driven post-transplant lymphoproliferative diseases (PTLDs). The term PTLD includes a heterogeneous group of conditions that occur in the post-transplant setting 72. Most, but not all, are EBV-associated; tumours occurring within a year or two of transplantation are much more likely to be EBV-positive than late-onset tumours. Morphologically, they are divided into reactive plasmacytic hyperplasias and lesions resembling IM; polymorphic PTLDs; monomorphic PTLDs, which are classified in accordance with lymphomas in immunocompetent persons; T-cell neoplasms; and HL 72. Polymorphic PTLDs show effacement of the lymph node architecture and infiltration with cells showing the full range of B-cell maturation. In monomorphic PTLD, there is sufficient architectural and cytological atypia to warrant the diagnosis of lymphoma on morphological grounds.

Most polymorphic and monomorphic B-cell PTLDs are EBV-associated. The tumour cells express the full spectrum of EBV latent genes (latency III) and these tumours therefore resemble B-cells transformed by EBV in vitro73. Most cases, even those categorized as polymorphic PTLD, have clonal Ig gene rearrangements and harbour clonal EBV genomes, although occasional early lesions may be polyclonal or oligoclonal 74. Even monoclonal tumours can respond to withdrawal of immunosuppressive treatment, suggesting that these lesions are purely virally driven and have not acquired secondary mutations. Late-onset PTLDs are less frequently EBV-associated and show a more variable pattern of EBV gene expression (latency I or II). Although no consistent cellular genetic changes have been detected in these cases, they are more likely to have detectable mutations of oncogenes or tumour suppressor genes than early lesions 72, 74. This is consistent with the idea that these tumours have evolved from LCL-like lesions but, following the acquisition of cellular mutations, are no longer dependent on the expression of all the viral latent genes.

Mutational analysis of the Ig gene rearrangements in B-cell PTLDs shows that they are largely derived from post-germinal centre B-cells, which have undergone somatic hypermutation 75. Other cases harbour crippling mutations of their Ig genes and are therefore unable to express surface BCR complexes 75. This resembles the situation seen in HL and suggests that rescue of B-cells with crippled Ig genes may be an important mechanism in the pathogenesis of EBV-associated lymphomas.

The risk of developing PTLD is increased in patients receiving higher dosages of immunosuppressive agents and anti-T-cell therapy 40. Primary EBV infection occurring at, or subsequent to, transplantation confers a particularly high risk and this is a serious problem in paediatric patients 40. A high viral load, or increasing viral load, appears to presage the development of PTLD and monitoring of viral load is advocated in patient management 76.

NK/T-cell lymphoma

Although EBV is clearly B-cell tropic in vitro, there is evidence from studies of T/NK cell lymphomas that EBV can infect T and NK cells in vivo; infection of T-cells appears to convey a particularly high risk of lymphoma 42. Extranodal NK/T-cell lymphomas and aggressive NK-cell leukaemias occur most commonly in South East Asia and parts of South America and are rare elsewhere, although they have been described in immunosuppressed patients 77, 78. NK/T-cell lymphomas of nasal type are always EBV-positive, irrespective of geographical origin 77, 79. The tumour cells consistently express EBNA1 and LMP2, whereas expression of LMP1 is more variable 42, 79. In Asian populations, NK/T-cell lymphoma occurring outside the nasal cavity is strongly associated with EBV but this association is less clear in white populations 77.

Human herpesvirus 8

  1. Top of page
  2. Abstract
  3. Introduction
  4. Human T-cell leukaemia virus type 1
  5. Epstein–Barr virus
  6. Human herpesvirus 8
  7. Human immunodeficiency virus
  8. Hepatitis C virus
  9. SV40
  10. Conclusions
  11. Acknowledgements
  12. References

HHV-8 (also known as KSHV) is a γ herpesvirus, which is distantly related to EBV. It is the causative agent of Kaposi's sarcoma and is also associated with several benign and malignant lymphoproliferative diseases. The identification of HHV-8 has led to the recognition of several somewhat rare lymphoproliferative diseases as discrete entities. A more complete description of HHV-8 is given elsewhere in this issue 80.

HHV-8 has been detected in two benign lymphoproliferations—a plasmablastic variant of multicentric Castleman's disease (MCD) and germinotropic lymphoproliferative disorder 81, 82. In MCD, the HHV-8 is localized to a unique population of IgM λ-positive plasmablasts, which are not found in non-HHV-8-associated forms of this disease 81. They are present in the mantle zone of follicles, occur singly or in clusters, and are not co-infected with EBV. HHV-8-positive plasmablastic lymphoma develops in some cases. Germinotropic lymphoproliferative disorder is characterized by polyclonal or oligoclonal aggregates of plasmablasts co-infected with HHV-8 and EBV within germinal centres 82.

PEL is a rare lymphoma that occurs in body cavities, usually without a contiguous tumour mass 83, 84. It is universally associated with HHV-8 and largely occurs in HIV-positive men with low CD4 cell counts 84. In the vast majority of cases, the tumour cells are infected by both HHV-8 and EBV. PELs are monoclonal B-cell proliferations which morphologically resemble immunoblastic or anaplastic large cell lymphoma; they frequently show plasmacytic differentiation and express CD138 and CD45, although they generally lack pan-B markers 84. A rare solid tumour occurring in the absence of an effusion, but with almost indistinguishable features from PEL, has been recognized more recently and designated extra-cavitary PEL 85.

Human immunodeficiency virus

  1. Top of page
  2. Abstract
  3. Introduction
  4. Human T-cell leukaemia virus type 1
  5. Epstein–Barr virus
  6. Human herpesvirus 8
  7. Human immunodeficiency virus
  8. Hepatitis C virus
  9. SV40
  10. Conclusions
  11. Acknowledgements
  12. References

The incidence of lymphoma is increased 60- to 200-fold in HIV-positive individuals and non-Hodgkin's lymphoma (NHL) is an AIDS-defining illness 84. HIV is a lentivirus of the retrovirus family and therefore replicates using a DNA intermediate which integrates into host cell chromosomal DNA 1. This virus is therefore inherently mutagenic; however, lymphomas with monoclonal integration of HIV have been described only rarely and, in the vast majority of cases, the role of HIV in lymphomagenesis is indirect and related to either immunosuppression or B-cell activation. EBV is associated with more than half the lymphomas occurring in the context of HIV infection; HHV-8 is involved more rarely (Table 1). The World Health Organization classification of HIV-associated lymphomas is shown in Table 184.

Table 1. Classification and herpesvirus involvement in lymphomas associated with HIV infection
Category of HIV-associated lymphoma% EBV-positive% HHV-8-positive
  • *

    Most data suggest that plasmablastic lymphoma of the oral cavity is HHV-8-negative, although one study reported detection of HHV-8 RNA within tumour cells 89. PTLD = post-transplant lymphoproliferative disease. Adapted from ref 84.

1. Lymphomas also occurring in immunocompetent patients
 Burkitt's lymphoma
 Classical∼30 
 With plasmacytoid differentiation50–70 
 Atypical30–50 
 Diffuse large B-cell lymphoma
 Centroblastic30 
 Immunoblastic90 
 MALT lymphoma (rare)
 Peripheral T-cell lymphoma (rare)
 Hodgkin lymphoma≤100 
2. Lymphomas occurring more specifically in HIV-positive patients
 Primary effusion lymphoma90100
 Plasmablastic lymphoma of the oral cavity>50*
3. Lymphomas also occurring in other immunodeficiency states
 Polymorphic B-cell lymphoma (PTLD-like)Most 

Classical BL accounts for approximately 30% of AIDS-related lymphomas and, in contrast to other AIDS-related lymphomas, often occurs early in the course of HIV infection 84. Like eBL, these tumours have chromosomal translocations involving the c-myc oncogene and a germinal centre phenotype; however, EBV is present in only a minority of cases—around 30% in western countries 84, 86. BL with plasmacytoid differentiation, which is almost unique to AIDS patients, and atypical BL are more frequently associated with EBV (Table 1). In EBV-positive cases, EBV latent antigen expression is generally restricted to the EBNA1 protein, although this appears less tightly controlled than in eBL.

The immunoblastic variant of diffuse large B-cell lymphoma occurs in individuals with severe immunosuppression and is associated with EBV in the vast majority of cases; primary central nervous system lymphomas are usually of this type and almost invariably EBV-associated 84. Similar to PTLD, most EBV-positive cases show a latency III pattern of EBV gene expression. DLBCLs with centroblastic morphology are more frequent but are less often associated with EBV 84, 86.

Plasmablastic lymphoma of the oral cavity is almost restricted to HIV-infected individuals 87. It is a clonal B-cell proliferation with immunoblastic morphology and strong expression of the plasma cell marker VS38c. EBV is detected in many, but not all, cases; EBNA2 expression is absent and LMP1 is expressed by only a small minority of cells, therefore the EBV expression pattern is predominantly that of latency type I 87. Most studies have not detected evidence of HHV-8 within these lymphomas 88, 89. Polymorphic lymphoid proliferations resembling those seen in the transplant setting also occur in HIV-positive individuals but are rare 84. Most, but not all, are EBV-associated.

Hepatitis C virus

  1. Top of page
  2. Abstract
  3. Introduction
  4. Human T-cell leukaemia virus type 1
  5. Epstein–Barr virus
  6. Human herpesvirus 8
  7. Human immunodeficiency virus
  8. Hepatitis C virus
  9. SV40
  10. Conclusions
  11. Acknowledgements
  12. References

HCV is a major cause of liver disease but has also been implicated in several extrahepatic disorders 90. There is very good evidence that it is associated with mixed cryoglobulinaemia, a lymphoproliferative disorder that sometimes evolves into B-cell NHL 90. The association between HCV and NHL is more controversial. Studies documenting a positive association have generally been performed in areas of high HCV prevalence, such as Italy; surveys carried out in low prevalence areas have frequently failed to detect evidence of HCV infection in NHL patients 90. Failure to detect an association may have resulted from small sample size in low prevalence areas and study design. Recent large case–control studies from both high and low prevalence areas have reported significant differences in HCV infection rates between cases and controls and therefore, on balance, this association appears real 91, 92. In a case–control study of 796 subjects attending hospitals in Italy, Mele et al detected evidence of viral infection in 17.5% of B-cell NHL cases compared with 5.6% of controls (odds ratio 3.1, confidence intervals 1.8–5.2) 91. Likewise, in a study of 1497 individuals in the US, Engels et al found significant differences between cases and controls, although only 3.9% of their NHL cases and 2.1% of controls had evidence of HCV infection (odds ratio 1.96, confidence intervals 1.07–4.03) 92. HCV is mainly associated with low-grade B-cell NHLs, particularly marginal zone lymphomas; an association with DLBCLs has also been reported 91, 92.

HCV is an RNA virus, which does not have a DNA intermediate in its life cycle and therefore cannot integrate into host cell DNA. It infects and replicates in hepatocytes but can also infect peripheral blood mononuclear cells 90. Despite this tropism, the role of the virus in lymphomagenesis is probably indirect and related to chronic antigenic stimulation.

SV40

  1. Top of page
  2. Abstract
  3. Introduction
  4. Human T-cell leukaemia virus type 1
  5. Epstein–Barr virus
  6. Human herpesvirus 8
  7. Human immunodeficiency virus
  8. Hepatitis C virus
  9. SV40
  10. Conclusions
  11. Acknowledgements
  12. References

SV40 is a primate polyomavirus that does not naturally infect humans but may have been introduced into human populations as a result of contamination of polio vaccines in the 1950s and early 1960s 93, 94. It is potently oncogenic in animal systems, where it causes a variety of malignancies including lymphomas 95. In 2002, two independent groups reported the detection of SV40 sequences in a high proportion (42% and 43%, respectively) of NHL samples using PCR 96, 97. Follow-up studies have not supported these findings. We failed to detect SV40 sequences in a series of 152 NHLs assayed using a sensitive TaqMan® assay for SV40 98. Capello et al similarly failed to detect consistent evidence of SV40 infection in 485 lymphoma specimens 99. Other investigators have detected SV40 genomes in an intermediate proportion of cases 100, 101. Using immunohistochemistry, Brousset et al did not detect evidence of SV40 large T antigen in any of the tumour cells of 232 NHL samples 102. In contrast, Vilchez and co-workers 103 detected SV40 large T antigen in 12/55 HIV-associated lymphomas but viral antigen was not detected within all tumour cells in an individual case. The reasons for the discrepant findings are not clear. Technical factors such as differences in assay sensitivity 104; contamination of DNA samples with SV40, particularly the large T sequences frequently found in plasmid vectors 105; and lack of specificity of large T antibodies are possible explanations. The lack of consistency of the findings (contrast this with the detection of EBV in HL or HHV-8 in PEL) suggests that SV40 is unlikely to be an important aetiological agent in NHL.

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Human T-cell leukaemia virus type 1
  5. Epstein–Barr virus
  6. Human herpesvirus 8
  7. Human immunodeficiency virus
  8. Hepatitis C virus
  9. SV40
  10. Conclusions
  11. Acknowledgements
  12. References

HTLV-1 and EBV are causally associated with leukaemia/lymphoma in man. These viruses belong to families with very different characteristics and epidemiological distributions. Despite this, there are many similarities in the mechanisms that they exploit to cause lymphoma. Both encode transactivator proteins that interact with cellular transcription factors and up-regulate expression of viral and cellular genes. Both cause activation of NF-κB, by interacting with classical and alternative pathways, leading to induction of cytokines, chemokines, and anti-apoptotic molecules. Both interact with proteins involved in cell cycle regulation and both inhibit TGF-β-mediated growth suppression. HHV-8 is associated with a small group of interesting and unusual lymphoproliferative disease. Although HHV-8 is related to EBV, the HHV-8 latent genes do not show any homology to EBV latent genes, although they have functional similarities. The incidence of lymphoma is greatly increased in individuals infected with HIV but here the mechanism is indirect. Over half the lymphomas occurring in the context of HIV infection are EBV-associated, while a small minority harbour HHV-8 and some are co-infected with HHV-8 and EBV. Recent data provide convincing evidence that HCV is associated with an increased incidence of NHL and here too the mechanism is likely to be indirect. The primate polyomavirus SV40 has also been linked to NHL but the evidence is controversial and this virus is unlikely to be causally associated with a significant proportion of lymphomas.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Human T-cell leukaemia virus type 1
  5. Epstein–Barr virus
  6. Human herpesvirus 8
  7. Human immunodeficiency virus
  8. Hepatitis C virus
  9. SV40
  10. Conclusions
  11. Acknowledgements
  12. References

I should like to thank Genoveffa Franchini and June Freeland for help with writing this review. Work in our laboratory is supported by the Leukaemia Research Fund.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Human T-cell leukaemia virus type 1
  5. Epstein–Barr virus
  6. Human herpesvirus 8
  7. Human immunodeficiency virus
  8. Hepatitis C virus
  9. SV40
  10. Conclusions
  11. Acknowledgements
  12. References
  • 1
    Goff SP. Retroviridae: the retroviruses and their replication. In Fields Virology (4th edn), KnipeDM, HowleyPM (eds). Lippincott Williams & Wilkins: Philadelphia, 2001; 18711939.
  • 2
    Green PL, Chen ISY. Human T-cell leukemia viruses types 1 and 2. In Fields Virology (4th edn), KnipeDM, HowleyPM (eds). Lippincott Williams & Wilkins: Philadelphia, 2001; 19411969.
  • 3
    Asher DM, Goudsmit J, Pomeroy KL, Garruto RM, Bakker M, Ono SG, et al. Antibodies to HTLV-I in populations of the southwestern Pacific. J Med Virol 1988; 26: 339351.
  • 4
    Azran I, Schavinsky-Khrapunsky Y, Priel E, Huleihel M, Aboud M. Implications of the evolution pattern of human T-cell leukemia retroviruses on their pathogenic virulence. Int J Mol Med 2004; 14: 909915.
  • 5
    Vandamme AM, Salemi M, Van BM, Liu HF, Van LK, Van RM, et al. African origin of human T-lymphotropic virus type 2 (HTLV-2) supported by a potential new HTLV-2d subtype in Congolese Bambuti Efe Pygmies. J Virol 1998; 72: 43274340.
  • 6
    Calattini S, Chevalier SA, Duprez R, Bassot S, Froment A, Mahieux R, et al. Discovery of a new human T-cell lymphotropic virus (HTLV-3) in central Africa. Retrovirology 2005; 2: 30.
  • 7
    Wolfe ND, Heneine W, Carr JK, Garcia AD, Shanmugam V, Tamoufe U, et al. Emergence of unique primate T-lymphotropic viruses among central African bushmeat hunters. Proc Natl Acad Sci U S A 2005; 102: 79947999.
  • 8
    Uchiyama T, Yodoi J, Sagawa K, Takatsuki K, Uchino H. Adult T-cell leukemia: clinical and hematologic features of 16 cases. Blood 1977; 50: 481492.
  • 9
    Matsuoka M. Human T-cell leukemia virus type I (HTLV-I) infection and the onset of adult T-cell leukemia (ATL). Retrovirology 2005; 2: 27.
  • 10
    Arisawa K, Soda M, Endo S, Kurokawa K, Katamine S, Shimokawa I, et al. Evaluation of adult T-cell leukemia/lymphoma incidence and its impact on non-Hodgkin lymphoma incidence in southwestern Japan. Int J Cancer 2000; 85: 319324.
  • 11
    Manns A, Cleghorn FR, Falk RT, Hanchard B, Jaffe ES, Bartholomew C, et al. Role of HTLV-I in development of non-Hodgkin lymphoma in Jamaica and Trinidad and Tobago. The HTLV Lymphoma Study Group. Lancet 1993; 342: 14471450.
  • 12
    Jolly C, Sattentau QJ. Retroviral spread by induction of virological synapses. Traffic 2004; 5: 643650.
  • 13
    Poiesz BJ, Poiesz MJ, Choi D. The human T-cell lymphoma/leukemia viruses. Cancer Invest 2003; 21: 253277.
  • 14
    Gaudray G, Gachon F, Basbous J, Biard-Piechaczyk M, Devaux C, Mesnard JM. The complementary strand of the human T-cell leukemia virus type 1 RNA genome encodes a bZIP transcription factor that down-regulates viral transcription. J Virol 2002; 76: 12 81312 822.
  • 15
    Grassmann R, Dengler C, Muller-Fleckenstein I, Fleckenstein B, McGuire K, Dokhelar MC, et al. Transformation to continuous growth of primary human T lymphocytes by human T-cell leukemia virus type I X-region genes transduced by a Herpesvirus saimiri vector. Proc Natl Acad Sci U S A 1989; 86: 33513355.
  • 16
    Iwanaga Y, Tsukahara T, Ohashi T, Tanaka Y, Arai M, Nakamura M, et al. Human T-cell leukemia virus type 1 tax protein abrogates interleukin-2 dependence in a mouse T-cell line. J Virol 1999; 73: 12711277.
  • 17
    Jeang KT, Giam CZ, Majone F, Aboud M. Life, death, and tax: role of HTLV-I oncoprotein in genetic instability and cellular transformation. J Biol Chem 2004; 279: 31 99131 994.
  • 18
    Harhaj EW, Harhaj NS. Mechanisms of persistent NF-kappaB activation by HTLV-I tax. IUBMB Life 2005; 57: 8391.
  • 19
    Ballard DW, Bohnlein E, Lowenthal JW, Wano Y, Franza BR, Greene WC. HTLV-I tax induces cellular proteins that activate the kappa B element in the IL-2 receptor alpha gene. Science 1988; 241: 16521655.
  • 20
    Siekevitz M, Feinberg MB, Holbrook N, Wong-Staal F, Greene WC. Activation of interleukin 2 and interleukin 2 receptor (Tac) promoter expression by the trans-activator (tat) gene product of human T-cell leukemia virus, type I. Proc Natl Acad Sci U S A 1987; 84: 53895393.
  • 21
    Mori N, Fujii M, Cheng G, Ikeda S, Yamasaki Y, Yamada Y, et al. Human T-cell leukemia virus type I tax protein induces the expression of anti-apoptotic gene Bcl-xL in human T-cells through nuclear factor-kappaB and c-AMP responsive element binding protein pathways. Virus Genes 2001; 22: 279287.
  • 22
    Kawakami H, Tomita M, Matsuda T, Ohta T, Tanaka Y, Fujii M, et al. Transcriptional activation of survivin through the NF-kappaB pathway by human T-cell leukemia virus type I tax. Int J Cancer 2005; 115: 967974.
  • 23
    Gatza ML, Chandhasin C, Ducu RI, Marriott SJ. Impact of transforming viruses on cellular mutagenesis, genome stability, and cellular transformation. Environ Mol Mutagen 2005; 45: 304325.
  • 24
    Akagi T, Ono H, Shimotohno K. Expression of cell-cycle regulatory genes in HTLV-I infected T-cell lines: possible involvement of Tax1 in the altered expression of cyclin D2, p18Ink4 and p21Waf1/Cip1/Sdi1. Oncogene 1996; 12: 16451652.
  • 25
    Haller K, Wu Y, Derow E, Schmitt I, Jeang KT, Grassmann R. Physical interaction of human T-cell leukemia virus type 1 Tax with cyclin-dependent kinase 4 stimulates the phosphorylation of retinoblastoma protein. Mol Cell Biol 2002; 22: 33273338.
  • 26
    Lemoine FJ, Marriott SJ. Accelerated G(1) phase progression induced by the human T cell leukemia virus type I (HTLV-I) Tax oncoprotein. J Biol Chem 2001; 276: 31 85131 857.
  • 27
    Pise-Masison CA, Mahieux R, Radonovich M, Jiang H, Brady JN. Human T-lymphotropic virus type I Tax protein utilizes distinct pathways for p53 inhibition that are cell type-dependent. J Biol Chem 2001; 276: 200205.
  • 28
    Jeang KT, Widen SG, Semmes OJ, Wilson SH. HTLV-I trans-activator protein, tax, is a trans-repressor of the human beta-polymerase gene. Science 1990; 247: 10821084.
  • 29
    Lemoine FJ, Kao SY, Marriott SJ. Suppression of DNA repair by HTLV type 1 Tax correlates with Tax trans-activation of proliferating cell nuclear antigen gene expression. AIDS Res Hum Retroviruses 2000; 16: 16231627.
  • 30
    Liu B, Hong S, Tang Z, Yu H, Giam CZ. HTLV-I Tax directly binds the Cdc20-associated anaphase-promoting complex and activates it ahead of schedule. Proc Natl Acad Sci U S A 2005; 102: 6368.
  • 31
    Hollsberg P, Ausubel LJ, Hafler DA. Human T cell lymphotropic virus type I-induced T cell activation. Resistance to TGF-beta 1-induced suppression. J Immunol 1994; 153: 566573.
  • 32
    Ye J, Silverman L, Lairmore MD, Green PL. HTLV-1 Rex is required for viral spread and persistence in vivo but is dispensable for cellular immortalization in vitro. Blood 2003; 102: 39633969.
  • 33
    Johnson JM, Nicot C, Fullen J, Ciminale V, Casareto L, Mulloy JC, et al. Free major histocompatibility complex class I heavy chain is preferentially targeted for degradation by human T-cell leukemia/lymphotropic virus type 1 p12(I) protein. J Virol 2001; 75: 60866094.
  • 34
    Matsuoka M. Human T-cell leukemia virus type I and adult T-cell leukemia. Oncogene 2003; 22: 51315140.
  • 35
    Okayama A, Stuver S, Matsuoka M, Ishizaki J, Tanaka G, Kubuki Y, et al. Role of HTLV-1 proviral DNA load and clonality in the development of adult T-cell leukemia/lymphoma in asymptomatic carriers. Int J Cancer 2004; 110: 621625.
  • 36
    Bangham CR. The immune control and cell-to-cell spread of human T-lymphotropic virus type 1. J Gen Virol 2003; 84: 31773189.
  • 37
    Kannagi M, Ohashi T, Harashima N, Hanabuchi S, Hasegawa A. Immunological risks of adult T-cell leukemia at primary HTLV-I infection. Trends Microbiol 2004; 12: 346352.
  • 38
    Rickinson AB, Kieff E. Epstein–Barr virus. In Fields Virology (4th edn), KnipeDM, HowleyPM (eds). Lippincott Williams & Wilkins: Philadelphia, 2001; 25752627.
  • 39
    Thorley-Lawson DA, Gross A. Persistence of the Epstein–Barr virus and the origins of associated lymphomas. N Engl J Med 2004; 350: 13281337.
  • 40
    Swinnen LJ. Post-transplant lymphoproliferative disorders: implications for acquired immunodeficiency syndrome-associated malignancies. J Natl Cancer Inst Monogr 2000; 28: 3843.
  • 41
    Kieff E, Rickinson AB. Epstein–Barr virus and its replication. In Fields Virology (4th edn), KnipeDM, HowleyPM (eds). Lippincott Williams & Wilkins: Philadelphia, 2001; 25112573.
  • 42
    Young LS, Rickinson AB. Epstein–Barr virus: 40 years on. Nature Rev Cancer 2004; 4: 757768.
  • 43
    Wilson JB, Bell JL, Levine AJ. Expression of Epstein–Barr virus nuclear antigen-1 induces B cell neoplasia in transgenic mice. EMBO J 1996; 15: 31173126.
  • 44
    Kang MS, Lu H, Yasui T, Sharpe A, Warren H, Cahir-McFarland E, et al. Epstein–Barr virus nuclear antigen 1 does not induce lymphoma in transgenic FVB mice. Proc Natl Acad Sci U S A 2005; 102: 820825.
  • 45
    Kennedy G, Komano J, Sugden B. Epstein–Barr virus provides a survival factor to Burkitt's lymphomas. Proc Natl Acad Sci U S A 2003; 100: 14 26914 274.
  • 46
    Zimber-Strobl U, Strobl LJ. EBNA2 and Notch signalling in Epstein–Barr virus mediated immortalization of B lymphocytes. Semin Cancer Biol 2001; 11: 423434.
  • 47
    Lam N, Sugden B. CD40 and its viral mimic, LMP1: similar means to different ends. Cell Signal 2003; 15: 916.
  • 48
    Kieser A, Kilger E, Gires O, Ueffing M, Kolch W, Hammerschmidt W. Epstein–Barr virus latent membrane protein-1 triggers AP-1 activity via the c-Jun N-terminal kinase cascade. EMBO J 1997; 16: 64786485.
  • 49
    Gires O, Kohlhuber F, Kilger E, Baumann M, Kieser A, Kaiser C, et al. Latent membrane protein 1 of Epstein–Barr virus interacts with JAK3 and activates STAT proteins. EMBO J 1999; 18: 30643073.
  • 50
    Caldwell RG, Brown RC, Longnecker R. Epstein-Barr virus LMP2A-induced B-cell survival in two unique classes of EmuLMP2A transgenic mice. J Virol 2000; 74: 11011113.
  • 51
    Portis T, Dyck P, Longnecker R. Epstein–Barr virus (EBV) LMP2A induces alterations in gene transcription similar to those observed in Reed–Sternberg cells of Hodgkin lymphoma. Blood 2003; 102: 41664178.
  • 52
    Fukuda M, Longnecker R. Latent membrane protein 2A inhibits transforming growth factor-beta 1-induced apoptosis through the phosphatidylinositol 3-kinase/Akt pathway. J Virol 2004; 78: 16971705.
  • 53
    Hislop AD, Annels NE, Gudgeon NH, Leese AM, Rickinson AB. Epitope-specific evolution of human CD8(+) T cell responses from primary to persistent phases of Epstein–Barr virus infection. J Exp Med 2002; 195: 893905.
  • 54
    Lee SP, Brooks JM, Al-Jarrah H, Thomas WA, Haigh TA, Taylor GS, et al. CD8 T cell recognition of endogenously expressed Epstein–Barr virus nuclear antigen 1. J Exp Med 2004; 199: 14091420.
  • 55
    Khan G, Lake A, Shield L, Freeland J, Andrew L, Alexander FE, et al. Phenotype and frequency of Epstein–Barr virus-infected cells in pretreatment blood samples from patients with Hodgkin lymphoma. Br J Haematol 2005; 129: 511519.
  • 56
    Moormann AM, Chelimo K, Sumba OP, Lutzke ML, Ploutz-Snyder R, Newton D, et al. Exposure to holoendemic malaria results in elevated Epstein–Barr virus loads in children. J Infect Dis 2005; 191: 12331238.
  • 57
    Berns A. Cancer: two in one. Nature 2005; 436: 787789.
  • 58
    Natkunam Y, Lossos IS, Taidi B, Zhao S, Lu X, Ding F, et al. Expression of the human germinal center-associated lymphoma (HGAL) protein, a new marker of germinal center B-cell derivation. Blood 2005; 105: 39793986.
  • 59
    Bellan C, Lazzi S, Hummel M, Palummo N, de Santi M, Amato T, et al. Immunoglobulin gene analysis reveals 2 distinct cells of origin for EBV-positive and EBV-negative Burkitt lymphomas. Blood 2005; 106: 10311036.
  • 60
    Glaser SL, Jarrett RF. The epidemiology of Hodgkin's disease. In Hodgkin's Disease (9th edn), DiehlV (ed). Bailliere Tindall: London, 1996; 401416.
  • 61
    Macfarlane GJ, Evstifeeva T, Boyle P, Grufferman S. International patterns in the occurrence of Hodgkin's disease in children and young adult males. Int J Cancer 1995; 61: 165169.
  • 62
    Gutensohn NM, Shapiro DS. Social class risk factors among children with Hodgkin's disease. Int J Cancer 1982; 30: 433435.
  • 63
    Jarrett RF. Viruses and Hodgkin's lymphoma. Ann Oncol 2002; 13(S1): 2329.
  • 64
    Weiss LM, Strickler JG, Warnke RA, Purtilo DT, Sklar J. Epstein–Barr viral DNA in tissues of Hodgkin's disease. Am J Pathol 1987; 129: 8691.
  • 65
    Jarrett RF, Armstrong AA, Alexander E. Epidemiology of EBV and Hodgkin's lymphoma. Ann Oncol 1996; 7: S5S10.
  • 66
    Kuppers R, Rajewsky K. The origin of Hodgkin and Reed/Sternberg cells in Hodgkin's disease. Annu Rev Immunol 1998; 16: 471493.
  • 67
    Chaganti S, Bell AI, Begue-Pastor N, Milner AE, Drayson M, Gordon J, et al. Epstein–Barr virus infection in vitro can rescue germinal centre B cells with inactivated immunoglobulin genes. Blood 2005; epub ahead of print.
  • 68
    Bechtel D, Kurth J, Unkel C, Kueppers R. Transformation of BCR-deficient germinal center B cells by EBV supports a major role of the virus in the pathogenesis of Hodgkin and post transplant lymphoma. Blood 2005; epub ahead of print.
  • 69
    Mancao C, Altmann M, Jungnickel B, Hammerschmidt W. Rescue of ‘crippled’ germinal center B cells from apoptosis by Epstein–Barr virus. Blood 2005; epub ahead of print.
  • 70
    Kilger E, Kieser A, Baumann M, Hammerschmidt W. Epstein–Barr virus-mediated B-cell proliferation is dependent upon latent membrane protein 1, which simulates an activated CD40 receptor. EMBO J 1998; 17: 17001709.
  • 71
    Schwering I, Brauninger A, Klein U, Jungnickel B, Tinguely M, Diehl V, et al. Loss of the B-lineage-specific gene expression program in Hodgkin and Reed–Sternberg cells of Hodgkin lymphoma. Blood 2003; 101: 15051512.
  • 72
    Harris NL, Swerdlow SH, Frizzera G, Knowles DM. Post-transplant lymphoproliferative disorders. In World Health Organisation Classification of Tumours: Pathology and Genetics of Tumours of Hematopoietic and Lymphoid Tissues, JaffeES, HarrisNL, SteinH, VardimanJW (eds). IARC: Lyon, 2001; 264271.
  • 73
    Young L, Alfieri C, Hennessy K, Evans H, O'Hara C, Anderson KC, et al. Expression of Epstein–Barr virus transformation-associated genes in tissues of patients with EBV lymphoproliferative disease. N Engl J Med 1989; 321: 10801085.
  • 74
    Knowles DM, Cesarman E, Chadburn A, Frizzera G, Chen J, Rose EA, et al. Correlative morphologic and molecular genetic analysis demonstrates three distinct categories of posttransplantation lymphoproliferative disorders. Blood 1995; 85: 552565.
  • 75
    Timms JM, Bell A, Flavell JR, Murray PG, Rickinson AB, Traverse-Glehen A, et al. Target cells of Epstein–Barr-virus (EBV)-positive post-transplant lymphoproliferative disease: similarities to EBV-positive Hodgkin's lymphoma. Lancet 2003; 361: 217223.
  • 76
    Stevens SJ, Vervoort MB, van den Brule AJ, Meenhorst PL, Meijer CJ, Middeldorp JM. Monitoring of Epstein–Barr virus DNA load in peripheral blood by quantitative competitive PCR. J Clin Microbiol 1999; 37: 28522857.
  • 77
    Chan JKC, Jaffe ES, Ralfkiaer E. Extranodal NK/T-cell lymphoma, nasal type. In World Health Organisation Classification of Tumours: Pathology and Genetics of Tumours of Hematopoietic and Lymphoid Tissues, JaffeES, HarrisNL, SteinH, VardimanJW (eds). IARC: Lyon, 2001; 204207.
  • 78
    Chan JKC, Wong KF, Jaffe ES, Ralfkiaer E. Aggressive NK-cell leukaemia. In World Health Organisation Classification of Tumours: Pathology and Genetics of Tumours of Hematopoietic and Lymphoid Tissues, JaffeES, HarrisNL, SteinH, VardimanJW (eds). IARC: Lyon, 2001; 198200.
  • 79
    Kanavaros P, de Bruin PC, Briere J, Meijer CJ, Gaulard P. Epstein–Barr virus (EBV) in extranodal T-cell non-Hodgkin's lymphomas (T-NHL). Identification of nasal T-NHL as a distinct clinicopathological entity associated with EBV. Leuk Lymphoma 1995; 18: 2734.
  • 80
    Schulz TF. The pleiotropic effects of Kaposi's sarcoma herpesvirus. J Pathol 2006; 208: 187198.
  • 81
    Dupin N, Diss TL, Kellam P, Tulliez M, Du MQ, Sicard D, et al. HHV-8 is associated with a plasmablastic variant of Castleman disease that is linked to HHV-8-positive plasmablastic lymphoma. Blood 2000; 95: 14061412.
  • 82
    Du MQ, Diss TC, Liu H, Ye H, Hamoudi RA, Cabecadas J, et al. KSHV- and EBV-associated germinotropic lymphoproliferative disorder. Blood 2002; 100: 34153418.
  • 83
    Nador RG, Cesarman E, Chadburn A, Dawson DB, Ansari MQ, Sald J, et al. Primary effusion lymphoma: a distinct clinicopathologic entity associated with the Kaposi's sarcoma-associated herpes virus. Blood 1996; 88: 645656.
  • 84
    Raphael M, Borisch B, Jaffe ES. Lymphomas associated with infection by the human immune deficiency virus (HIV). In World Health Organisation Classification of Tumours: Pathology and Genetics of Tumours of Hematopoietic and Lymphoid Tissues, JaffeES, HarrisNL, SteinH, VardimanJW (eds). IARC: Lyon, 2001; 260263.
  • 85
    Chadburn A, Hyjek E, Mathew S, Cesarman E, Said J, Knowles DM. KSHV-positive solid lymphomas represent an extra-cavitary variant of primary effusion lymphoma. Am J Surg Pathol 2004; 28: 14011416.
  • 86
    Hamilton-Dutoit SJ, Raphael M, Audouin J, Diebold J, Lisse I, Pedersen C, et al. In situ demonstration of Epstein–Barr virus small RNAs (EBER 1) in acquired immunodeficiency syndrome-related lymphomas: correlation with tumor morphology and primary site. Blood 1993; 82: 619624.
  • 87
    Delecluse HJ, Anagnostopoulos I, Dallenbach F, Hummel M, Marafioti T, Schneider U, et al. Plasmablastic lymphomas of the oral cavity: a new entity associated with the human immunodeficiency virus infection. Blood 1997; 89: 14131420.
  • 88
    Carbone A, Gloghini A, Gaidano G. Is plasmablastic lymphoma of the oral cavity an HHV-8-associated disease? Am J Surg Pathol 2004; 28: 15381540.
  • 89
    Cioc AM, Allen C, Kalmar JR, Suster S, Baiocchi R, Nuovo GJ. Oral plasmablastic lymphomas in AIDS patients are associated with human herpesvirus 8. Am J Surg Pathol 2004; 28: 4146.
  • 90
    Mazzaro C, Tirelli U, Pozzato G. Hepatitis C virus and non-Hodgkin's lymphoma 10 years later. Dig Liver Dis 2005; 37: 219226.
  • 91
    Mele A, Pulsoni A, Bianco E, Musto P, Szklo A, Sanpaolo MG, et al. Hepatitis C virus and B-cell non-Hodgkin lymphomas: an Italian multicenter case–control study. Blood 2003; 102: 996999.
  • 92
    Engels EA, Chatterjee N, Cerhan JR, Davis S, Cozen W, Severson RK, et al. Hepatitis C virus infection and non-Hodgkin lymphoma: results of the NCI–SEER multi-center case–control study. Int J Cancer 2004; 111: 7680.
  • 93
    Shah K, Nathanson N. Human exposure to SV40: review and comment. Am J Epidemiol 1976; 103: 112.
  • 94
    Sangar D, Pipkin PA, Wood DJ, Minor PD. Examination of poliovirus vaccine preparations for SV40 sequences. Biologicals 1999; 27: 110.
  • 95
    Butel JS, Lednicky JA. Cell and molecular biology of simian virus 40: implications for human infections and disease. J Natl Cancer Inst 1999; 91: 119134.
  • 96
    Vilchez RA, Madden CR, Kozinetz CA, Halvorson SJ, White ZS, Jorgensen JL, et al. Association between simian virus 40 and non-Hodgkin lymphoma. Lancet 2002; 359: 817823.
  • 97
    Shivapurkar N, Harada K, Reddy J, Scheuermann RH, Xu Y, McKenna RW, et al. Presence of simian virus 40 DNA sequences in human lymphomas. Lancet 2002; 359: 851852.
  • 98
    MacKenzie J, Wilson KS, Perry J, Gallagher A, Jarrett RF. Association between simian virus 40 DNA and lymphoma in the United Kingdom. J Natl Cancer Inst 2003; 95: 10011003.
  • 99
    Capello D, Rossi D, Gaudino G, Carbone A, Gaidano G. Simian virus 40 infection in lymphoproliferative disorders. Lancet 2003; 361: 8889.
  • 100
    Martini F, Dolcetti R, Gloghini A, Iaccheri L, Carbone A, Boiocchi M, et al. Simian-virus-40 footprints in human lymphoproliferative disorders of HIV− and HIV+ patients. Int J Cancer 1998; 78: 669674.
  • 101
    Nakatsuka S, Liu A, Dong Z, Nomura S, Takakuwa T, Miyazato H, et al. Simian virus 40 sequences in malignant lymphomas in Japan. Cancer Res 2003; 63: 76067608.
  • 102
    Brousset P, de Araujo V, Gascoyne RD. Immunohistochemical investigation of SV40 large T antigen in Hodgkin and non-Hodgkin's lymphoma. Int J Cancer 2004; 112: 533535.
  • 103
    Vilchez RA, Lopez-Terrada D, Middleton JR, Finch CJ, Killen DE, Zanwar P, et al. Simian virus 40 tumor antigen expression and immunophenotypic profile of AIDS-related non-Hodgkin's lymphoma. Virology 2005; 342: 3846.
  • 104
    McNees AL, White ZS, Zanwar P, Vilchez RA, Butel JS. Specific and quantitative detection of human polyomaviruses BKV, JCV, and SV40 by real time PCR. J Clin Virol 2005; 34: 5262.
  • 105
    Lopez-Rios F, Illei PB, Rusch V, Ladanyi M. Evidence against a role for SV40 infection in human mesotheliomas and high risk of false-positive PCR results owing to presence of SV40 sequences in common laboratory plasmids. Lancet 2004; 364: 11571166.