Epstein-Barr Virus

Epstein-Barr virus (EBV) is a member of the human herpesvirus subfamily Gammaherpesviridae. EBV is an enveloped virus with a double-stranded DNA genome of 172 kilobases (kb) containing more than 100 genes. EBV is a ubiq-uitons virus that infects and persists in about 90% of the world's human population. EBV selectively infects mature B lymphocytes, the only cells bearing the CD21 receptor for virus attachment, recognized by the viral envelope glycoprotein gp350.5 However, natural killer (NK) cells can also be infected with EBV and are associated with unusual malignancies of these cell types. Primary infection with EBV usually occurs in childhood. In most cases, the clinical course is unapparent. In a subset of infected individuals, primary EBV infection can result in infectious mononucleosis, a self-limited lymphoproliferative disease. The syndrome of mononucleosis is more frequent when primary infection is delayed into adolescence. Once infected, individuals become lifelong virus carriers and, when the virus has gained access to the B-cell compartment, it is disseminated to many organs including liver, Bm, and central nervous system (CNS). B cells are eliminated by specific cytotoxic T cells, and T-cell immunosuppression can lead to the development of EBV-

associated malignant lymphomas. However, EBV is also associated with the development of lymphoid and epithelial malignancies in apparently immunocompetent hosts.6

After infection, EBV enters a latent state, with or without a minimal production of viral progeny. During latency the viral genome remains in an episomal state, sometimes with rare viral DNA molecules integrated into the cell genome.5 Latent infection by EBV causes the immortalization of B lymphocytes, which lose the ability to achieve terminal differentiation. EBV-infected B lymphocytes produce antibodies but never reach the stage of plasma cells.5 During latency, EBV expresses only some of its genes: six proteins localized in the nucleus and called Epstein-Barr nuclear antigens (EBNA) 1, -2, -3A, -3B, -3C, and leader protein (LP); three proteins localized in the cytoplasmic membrane, called latent membrane proteins (LMPs) 1, -2A, -2B; two small noncoding RNAs (EBER-1 and EBER-2); and the BARF1 gene, located in the BamHI-A region of the viral genome.5 Several of these genes are expressed in EBV-immortalized lymphoblastoid cell lines and in EBV-associated malignancies.5,6 These genes have activities that may contribute to the deregulation of normal cell growth and to oncogenesis. EBNA-1 is a DNA-binding protein that is postulated to act as a transcriptional activator of the cellular recombinase-activating genes RAG-1 and RAG-2,7 which in turn lead to chromosomal translocations within the host cell. The main function of EBNA-1 is maintenance of the EBV episome during cell division. EBNA-2 (in concert with EBNA-LP) also functions as a transcriptional activator that induces the expression of CD21, which encodes the cellular EBV receptor, and CD23, the tyrosine kinase c-fgr, cyclin D2, and all the other latent EBV genes, including the LMP-1, LMP-2A, and LMP-2B.5,6,8 LMP-4 by itself cannot transform human cells. LMP-1 transforms rodent cells and is necessary for transformation of human cells; it has multiple effects, including increased expression of cellular adhesion molecules, upregulation of lymphocyte activation antigens, and stimulation of the transcription factors, such as API and NF-kB.5,6

The human lymphoid malignancies associated with EBV infection are Burkitt's lymphoma, B-cell lymphomas in immunocompromised individuals, T-cell lymphomas, the X-linked lymphoproliferative disease, and Hodgkin's disease.9-15 Lymphocyte immortalization induced by EBV and the acquisition of an indefinite life span may increase the probability of accumulating genetic alterations that can lead to malignancy. In fact, EBV-positive lymphomas typically develop specific chromosomal translocations involving the regulatory sequences of the immunoglobulin genes on chromosome 14q32 (76% of cases), 22q11 (16% of cases), or 2p11 (8% of cases), which are joined to the c-myc proto-oncogene on chromosome 8q24.16 These translocations cause the deregulated activation of c-myc expression and are the basis for oncogenicity in BL. c-myc activation renders the proliferation of EBV-immortalized cells independent of LMP1 and EBNA2 expression.17 EBV infection may favor, but is not a necessary prerequisite, for the rearrangement of c-myc and for lymphoma development, because rare cases of endemic Burkitt's lymphoma (BL) in equatorial Africa are EBV negative.18,19 Moreover, only 15% to 20% sporadic BL in the Western world are EBV positive whereas all BL contain the typical c-myc translocations.20 EBV-associated B-cell lymphomas occur with notable frequency in patients with acquired immunodeficiency syndrome (AIDS), and 65% to 100% of AIDS lymphomas, especially brain lymphomas, contain EBV DNA. These tumors, in addition to c-myc translocations, often contain c-ras mutations, p53 inactivation by deletion or point mutation, and bcl-6 rearrangements.21,22 A similar set of molecular alterations was described in EBV-positive lympho-proliferative disorders and lymphomas arising in immuno-suppressed transplant patients.23 I think EBV by itself is able to drive these proliferative conditions. They are initially poly-clonal, and through selection become monoclonal and autonomous, that is, no longer responsive to reduction of immunosuppressive drugs. These findings support the notion that multiple genetic alterations are required for the development of the transformed phenotype. EBV, by contributing to some of these genetic changes, increases the risk of these tumors in infected individuals.

The X-linked lymphoproliferative disease (XLP) or Duncan's disease is a hereditary syndrome caused by the alteration of a gene located at chromosome region Xq25.24,25 The XLP gene, called SH2D1A, was recently cloned,25 and its product regulates the interaction between B and T lymphocytes. Mutations in the SH2D1A gene, detected in XLP patients, generate a state of immune dysfunction that induces an altered response to viral infections, especially to EBV. XLP patients, when infected with EBV, develop in approximately 65% of cases a severe form of infectious mononucleosis that is fatal in 70% of children less than 10 years of age.25 Most surviving patients develop a lymphoproliferative disorder or a lymphoma, and a few develop aplastic anemia or vasculi-

tis.25 The pathogenesis of the disease is related to an enhanced response to EBV infection.25 Following infection with EBV, normal individuals develop a T-cell response to EBV-infected B cells with elevated serum levels of TH-1 cytokines, such as interferon-g and IL-2. This response is greatly increased in XLP patients,26 and the dysregulated TH-1 response is considered the most important pathogenetic event that causes fulminant infectious mononucleosis. The malignant lymphomas arising in XLP patients are non-Hodgkin's B-cell lymphomas of the Burkitt's type and diffuse large cell lym-phomas.24 The expression of EBV genes has not been studied in detail in XLP lymphomas, and the pathogenic role of EBV in these tumors is under investigation.

In Hodgkin's disease (HD), EBV involvement is supported by the presence of EBV DNA in 26% to 67% of sporadic cases and in 100% of HD arising in AIDS patients.13,27 Episomal EBV DNA is detected in the multinucleated Reed-Sternberg cells, the malignant neoplastic giant cells of HD that are required for the histopathologic diagnosis of the disease. The EBV genome is detected also in Hodgkin cells, the mono-nuclear giant cells that are considered the precursors of Reed-Sternberg cells. In HD, Reed-Sternberg and Hodgkin cells represent clonal expansions of EBV-infected cells. The oncogene EBV LMP-1 is expressed within Reed-Sternberg cells and their precursors, whereas EBNA-2 is not expressed.13,27 The function of EBNA-1 is to maintain the EBV episome, from which the various EBV onco-proteins are expressed. LMP-1, the most potent EBV oncogene, seems to play an important role in the pathogenesis of HD.13 In addition to the EBV-infected Hodgkin and Reed-Sternberg cells, the pathologic tissue contains macrophages, B and T-lym-phocytes that outnumber the malignant cells. In this context, the EBV antigens expressed in HD neoplastic cells may stimulate the reactive cellular component of the disease to secrete cytokines and other biologic mediators that could favor the growth and the expansion of tumor cells.13

EBV can also infect nonlymphoid cells, such as epithelial and, in children with AIDS, muscle cells, which are devoid of the CD21 receptor. EBV probably infects these cells by fusion or cell-to-cell contact with EBV-infected lymphocytes.5,28 Thus, EBV can contribute to the development of some types of epithelial cancers, such as nasopharyngeal carcinoma (NPC).9,14,15 Undifferentiated NPC accounts for up to 80% of all NPC and occurs with high prevalence in certain regions of East Asia, such as Southern China. Clustering of this tumor in these specific geographic areas is probably a result of a combination of genetic predisposition and lifestyle factors.14,15 Detection of IgA antibodies against the EBV viral capsid antigen, a rare finding in the normal population, has been successfully employed as a marker of increased tumor risk in screening programs in high-incidence areas.14,15 Multiple copies of monoclonal EBV episomes are present in every cell of NPCs,14,15 whereas integrated EBV DNA has been detected only in a fraction of NPC.28,29 Immunoblotting demonstrates LMP-1 protein in 65% or more NPC, and LMP-1 transcripts are detectable in virtually all cases by polymerase chain reaction (PCR) analysis.14,15,30 EBNA-1 is expressed in essentially all NPC cells. Other nonlymphoid malignancies possibly associated with EBV are gastric carcinoma, leiomyoma, and leiomyosarcoma. In gastric carcinoma, the viral DNA is found in approximately 90% of the rare gastric lymphoepithelioma-like carcinomas and in about 10% of the common gastric ade-

TABLE 17.2. Mechanisms of transformation by Epstein-Barr virus.

First phase

Second phase

Third phase

Expression of viral antigens EBNA1, EBNA2

Was this article helpful?

0 0
10 Ways To Fight Off Cancer

10 Ways To Fight Off Cancer

Learning About 10 Ways Fight Off Cancer Can Have Amazing Benefits For Your Life The Best Tips On How To Keep This Killer At Bay Discovering that you or a loved one has cancer can be utterly terrifying. All the same, once you comprehend the causes of cancer and learn how to reverse those causes, you or your loved one may have more than a fighting chance of beating out cancer.

Get My Free Ebook

Post a comment