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Bast RC Jr, Kufe DW, Pollock RE, et al., editors. Holland-Frei Cancer Medicine. 5th edition. Hamilton (ON): BC Decker; 2000.

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Holland-Frei Cancer Medicine. 5th edition.

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Chapter 19Herpesviruses

, MD.

Eight herpesviruses have been isolated from humans. Herpes simplex 1, herpes simplex 2, and varicella-zoster virus are members of the alphaherpesvirus subfamily. Cytomegalovirus, human herpesvirus 6, and human herpesviruses 7 are betaherpesviruses, and Epstein-Barr virus (EBV) and human herpesvirus 8 (HHV-8, Kaposi’s sarcoma–associated herpesvirus) are gammaherpesviruses. Two of these herpesviruses have been associated with human tumors. EBV has been detected in lesions from patients with nasopharyngeal carcinoma, Burkitt’s lymphoma, Hodgkin’s disease, and certain other lymphoid tumors. HHV-8 is associated with Kaposi’s sarcoma, primary effusion lymphoma, and Castleman’s disease.

Herpesviruses are ubiquitous in nature, and nearly every animal species is infected by at least one herpesvirus. The transforming animal herpesviruses include Herpesvirus saimiri, which induces fatal T-cell lymphomas in certain species of monkeys and rabbits and transforms human T cells in vitro, and murine herpesvirus 68, which causes lymphoproliferative lesions in mice.

Properties of Herpesviruses

Herpesviruses are enveloped virions, which contain a DNA core surrounded by an icosahedral nucleocapsid and a tegument. The viral genome consists of linear, double-stranded DNA varying in size from 120 to 240 kilobase pairs, depending on the virus. The smallest herpesviruses contain approximately 70 unique genes, while the largest contain about 200 genes. Virions contain 30 to 35 structural proteins.

Infection of cells with herpesviruses begins with adsorption and fusion of the virion envelope with the cell membrane. The envelope glycoproteins are important mediators of adsorption and fusion. The viral capsid is released into the cytoplasm and is transported to the nucleus where the linear viral DNA circularizes. In infections that result in production of progeny viruses and lysis of the host cell, immediate-early, early, and subsequently late viral genes are transcribed in the nucleus and their proteins are synthesized in the cytoplasm, while translation of host cell RNAs is inhibited. Early lytic replication is associated with irreversible cytocidal inhibition of host DNA, RNA, and protein synthesis. Virion DNA is replicated and assembled into nucleocapsids in the nucleus. Nucleocapsids undergo initial envelopment by budding through the inner lamella of the nuclear membrane. Viral proteins and glycoproteins modify the host cell’s cytoplasmic membranes. Virions are released by exocytosis or by cytoplasmic de-envelopment and re-envelopment at the plasma membrane.

All herpesviruses have the capacity to establish latent infection as well as to undergo lytic infection. The capacity to establish latent infection in vivo and to reactivate from latency ensures a source of virus to infect previously uninfected individuals. Herpesviruses are ubiquitous in most human populations. Almost all adults latently harbor herpes simplex 1, varicella-zoster virus, human herpesvirus 6 and 7, and EBV. Reactivation in adults results in transmission of virus to infants, children, or young adults, perpetuating nearly uniform adult infection and persistence of the virus over many generations.

Oncogenic Features of Herpesviruses

Several features of herpesvirus replication are important for the maintenance of latency and for oncogenicity. In order to be oncogenic, herpesviruses must be able to maintain their viral genome in the cell, avoid killing the cell, avoid destruction of the cell by the immune system, and activate appropriate cellular growth control regulatory pathways. Since EBV is the best-studied of the human herpesviruses, which latently infects cells and has a strong association with human neoplasia, this virus will be used to illustrate the principles of herpesvirus infection relevant to oncogenicity.

First, viral DNA must be maintained in the cell. EBV establishes latent infection in B lymphocytes. Since B lymphocytes replicate, the virus must have a way to ensure transmission to cell progeny. The EBV genome is usually maintained in B cells either as a multicopy circular episome in the host cell, or the viral DNA can integrate into the host genome. Episomes are formed by fusion of the direct repeat sequences which are present at both termini of the linear genome present in virions. The Namalwa Burkitt tumor cell line contains a complete copy of the entire EBV genome integrated into the host cell DNA and no additional episomal viral DNA. Analysis of the DNA sequence indicates that the viral genome is integrated into the host DNA at the terminal direct repeat sequence of the virus.

Second, a cell transformed by a virus must avoid immune clearance. To achieve this, a virus can only express a limited number of viral genes. Replication of herpesviruses in cells results in inhibition of host cell protein synthesis and lysis of the host cell. Analysis of the EBV DNA sequence indicates nearly 100 possible gene products; however, latent infection of B cells with EBV results in expression of only 10 or fewer genes.1 This limited repertoire of gene products prevents frequent viral replication, with death of the infected cell, and restricts the ability of the immune system to recognize and destroy a cell latently infected with the virus.

Third, specific viral proteins interact with other cell proteins or directly transactivate other cell genes to provide additional functions necessary for immortalization. Proteins encoded by several DNA tumor viruses transactivate expression of cell genes which may be important to initiate or maintain neoplasia. Several EBV proteins interact with cellular proteins to activate transcription of viral and cellular genes or to engage signal transduction pathways in the cell (see below).

Epstein-Barr Virus: An Oncogenic Human Herpesvirus

Effect on B-cell Growth in vitro

Infection of primary B cells with EBV in vitro results in transformation of the cells, which can then proliferate indefinitely. B-cell activation antigens, including the CD23 cell surface protein, are expressed on the surface of the lymphoblastoid cells. While CD23 is expressed on the surface of EBV-transformed B cells, it is not present on normal resting B cells. The supernatant of EBV-transformed B cells contains a 35 kDa protein thought to represent a soluble, cleaved form of CD23. The soluble, cleaved form of CD23 may possess autocrine growth factor activity in EBV-transformed B cells.2 Other evidence that antibodies to CD23 can block the uptake of B cell growth factor on the surface of the B cells, suggests that CD23 could be a receptor for B cell growth factor.3 EBV infection of Burkitt’s lymphoma cells in vitro results in upregulation of a number of cellular proteins, including CD44, and two G protein–coupled peptide receptors.4

Gene Expression in Transformed Lymphocytes

Six different EBV nuclear proteins, two membrane proteins, and two nontranslated RNAs are known to be expressed in latently infected B lymphocytes that have been growth transformed by EBV in vitro. The EBV nuclear proteins, EBNA-1, EBNA-2, EBNA-LP, EBNA-3A, EBNA-3B, and EBNA-3C comprise the EBV nuclear antigen complex. EBNA-1 binds to the oriP (origin of viral DNA replication) sequence of EBV and allows the virus genome to be maintained as an episome in transformed B cells.5 Binding of EBNA-1 to oriP also has a small effect on transactivation of oriP as a cis enhancer of transcription.6 EBNA-1 transcripts are initiated from one of three different promoters. The Cp and Wp promoters are used to express EBNA-1 in lymphoblastoid cell lines in vitro, while the Fp promoter is used in tissues from Burkitt’s lymphoma, nasopharyngeal carcinoma, and Hodgkin’s disease.7–9 Transgenic mice expressing EBNA-1 develop B-cell lymphomas.10 EBNA-1 inhibits its own protein degradation by proteosomes,11 and the reduced processing and presentation of EBNA-1 peptides to major histocompatibility complex (MHC) class I molecules may allow cells expressing this protein to avoid destruction by cytotoxic T cells.

EBNA-2 is required for B-cell transformation by EBV. EBNA-2 transactivates expression of the EBV genes LMP-112 and LMP-2,13 and the cellular genes CD23, CD21,14 and c-fgr15 which encodes a protein tyrosine kinase and is a member of the src gene family. EBNA-2 does not bind DNA directly but interacts with several cellular proteins. EBNA-2 is targeted to the LMP-1, LMP-2, Cp EBNA, and CD23 promoters by the GTGGGAA-binding protein Jκ, and thereby activates these promoters.16 This protein plays a critical role in B-cell transformation by the virus. EBNA-2 also interacts with the DNA-binding protein PU-1 to transactivate the LMP-1 promoter.17 The transactivation domain of EBNA-2 is essential for B-lymphocyte transformation.18 This domain interacts with transcription factor TFIIB and the TATA-binding protein-associated factor TAF40.19 EBNA-2 is a major determinant of the type-specific transforming difference between the two naturally occurring types of EBV.18

EBNA-LP enhances the ability of EBNA-2 to transactivate LMP-1.19a While EBNA-LP binds to the retinoblastoma protein, heat shock proteins, and p53 in vitro,20 the significance of these interactions is uncertain at present. Deletion of the carboxy terminus of EBNA-LP markedly reduces the ability of the virus to transform B lymphocytes.21

EBNA-3A, EBNA-3B, and EBNA-3C are encoded by three tandem open-reading frames. These three proteins are distantly related. The EBNA-3 proteins bind to Jκ and prevents it from binding DNA, thereby inhibiting transactivation by EBNA-2.22 EBNA-3C is a regulator of transcription.23 EBNA-3A and EBNA-3C are essential for B-lymphocyte transformation in vitro,24 while EBNA-3B is dispensable.25

Two latent membrane proteins, LMP-1 and LMP-2, are expressed in B cells that have been growth transformed by EBV. LMP-1 functions as a transforming oncogene when transfected into rodent cell lines and in nude mice.26 Expression of LMP-1 in EBV-negative Burkitt’s lymphoma cells results in B-cell clumping and increased villous projections. Upregulation of Bcl-2 and A20 by LMP-1 in B cells protects the cells from apoptosis.27,28 Expression of LMP-1 in epithelial cells inhibits differentiation of the cells.29

LMP-1 interacts with several cellular proteins. LMP-1 is a functional homologue of CD40, a member of the tumor necrosis factor receptor (TNFR) family. The carboxy terminus of LMP-1 interacts with the TNFR-associated factors (TRAFs) 1,2,3, and 5 and TRADD in vitro.30,31 LMP-1 functions as a constitutively active form of CD40, resulting in activation of NF-kappaB and stress-activated protein kinases, adhesion molecules, the B7 co-stimulatory molecule, c-jun N-terminal kinase, and B-cell proliferation.32 LMP-1 also associates with vimentin, to form a patch in the cytoplasmic membrane of the B cell.

LMP-1 is essential for transformation of B lymphocytes by EBV.33 Expression of LMP-1 in the skin of transgenic mice induces epithelial hyperplasia with increased expression of keratin 6.34 Expression of LMP-1 in lymphocytes of transgenic mice results in the development of B-cell lymphomas; these tumors contain elevated levels of the antiapoptotic proteins Bcl-2 and A20.35 Analysis of EBV-containing lymphomas shows that LMP-1 localizes with TRAF-1, TRAF-3, and that activated NF-κB is present, suggesting that these activities may have an important role in oncogenesis.36

LMP-2 is a tyrosine-phosphorylated membrane protein that co-localizes with LMP-1 in B cells. Two forms of LMP-2 (LMP-2A and LMP-2B), which differ only in their first exon, are expressed in latently infected B cells. LMP-2 is expressed in latently infected peripheral blood lymphocytes in humans37 and is dispensable for B-cell transformation by EBV in vitro.38 LMP-2 is tyrosine phosphorylated and associates with the src family and syk protein-tyrosine kinases39 that are coupled to the B-cell receptor complex. B cells from transgenic mice expressing LMP-2 survive even without normal B-cell receptor signaling activity.40

LMP-2 prevents lytic reactivation of EBV-infected primary B cells and calcium mobilization in response to activation of the B-cell receptor complex by crosslinking of surface immunoglobulin. This effect is mediated by the ability of LMP-2 to block protein tyrosine phosphorylation, with failure to activate the src family, lyn, and syk protein-tyrosine kinases.39,41

The two EBV-encoded RNAs, EBER-1 and EBER-2, are the two most abundant EBV RNAs in latently infected B cells; however, they have no role in latent or lytic EBV infection or cell transformation in vitro.42 These RNAs are not polyadenylated and interact with the nuclear antigens La and EAP, ribosome protein L22, the double-stranded RNA–activated protein kinase, and interferon-inducible oligoadenylate synthetase.43,44

Epstein-Barr Virus Genes Expressed During Productive Infection

Infection of epithelial cells with EBV results in productive infection, with replication of virus and lysis of infected cells. Immediate-early genes encode regulators of virus gene expression, including ZEBRA, which acts as a switch to initiate lytic infection (Fig. 19.1).45 Early genes encode proteins that are involved in viral DNA synthesis, such as the viral DNA polymerase and thymidine kinase. Late genes encode structural proteins of the virus, including the viral capsid antigen and the major envelope glycoprotein gp350. Three viral genes expressed during productive infection are functional homologues of cellular genes and are important for the survival of EBV-infected B cells.

Figure 19.1. The structure of the Epstein-Barr virus genome with selected genes expressed during replication and latency.

Figure 19.1

The structure of the Epstein-Barr virus genome with selected genes expressed during replication and latency. The Epstein-Barr virus genome consists of 172 kilobase pairs of DNA (top line) and contains unique regions (U1–5), terminal repeats (TR), (more...)

The EBV BCRF-1 protein is highly homologous to interleukin-10 and has interleukin-10 activity.46 Recombinant BCRF-1 and BCRF-1 secreted from EBV-infected cells inhibit interferon-gamma release from activated human peripheral blood mononuclear cells and secretion of interleukin-12 from macrophages.46,47 Since interferon-gamma has been shown to inhibit outgrowth of EBV-infected B cells in vitro, expression of BCRF-1 during lytic infection may prevent activation of the immune system with subsequent destruction of other latently infected cells. BCRF-1 protein also acts as a B-cell growth factor.

The EBV BARF-1 protein acts as a soluble receptor for colony stimulating factor 1.48 BARF-1 inhibits interferon-alpha secretion by human monocytes. Since interferon-alpha inhibits outgrowth of EBV-infected B cells in vitro, BARF-1 may act in concert with BCRF-1 to inhibit interferon and promote increased survival of EBV-infected cells.

The EBV BHRF-1 protein is homologous to Bcl-2, a cellular protein that is activated in follicular lymphomas and protects cells from apoptosis. BHRF-1 co-localizes with Bcl-2 in the cytoplasm and protects Burkitt’s lymphoma cells from apoptosis.28

Animal Models

Several animal models have been used to study EBV oncogenesis. First, EBV-infected cell lines produce B-cell tumors when inoculated intracerebrally into nude mice.49 Second, inoculation of peripheral blood leukocytes from EBV-seropositive humans into mice with severe combined immunodeficiency results in development of human B-cell lymphomas in the animals. Inoculation of these mice with peripheral blood leukocytes from EBV-seronegative humans results in engraftment of a functional human immune system, and if these latter mice are subsequently injected with cell-free EBV, the animals develop immunoblastic lymphomas. These B-cell tumors express the full complement of EBNA and LMP genes characteristic of latently infected, growth-transformed cell lines.50

In the third model, cotton-top tamarins inoculated with a large dose of cell-free EBV develop multifocal large cell lymphomas over the ensuing few weeks. These tumors express EBNA-1, EBNA-2, EBNA-LP, and LMP-151 and are monoclonal or oligoclonal in origin. This model has been used to test the efficacy of candidate EBV vaccines. Recently, oral inoculation of seronegative rhesus monkeys with an EBV-like rhesus monkey virus resulted in a mononucleosis-like syndrome with establishment of latent infection.52

Clinical Aspects

Introduction

EBV infection is usually spread by saliva. The virus infects oropharyngeal cells and spreads to subepithelial B cells. During primary infection, up to a few percent of the peripheral blood B lymphocytes are infected with EBV and have the capacity to proliferate indefinitely in vitro. Natural killer (NK) cells, suppressor T cells, and HLA- and EBNA- or LMP-restricted cytotoxic T cells control the latently infected B lymphocytes. T- and B-cell interactions release lymphokines and cytokines, giving rise to many of the clinical manifestations of acute infectious mononucleosis. After recovery, the fraction of B cells latently infected with EBV in the peripheral blood remains at 1 in 105 to 1 in 106. These lymphocytes are the primary site of EBV persistence and a source of virus for persistent infection of epithelial surfaces.

B-cell tumors which occur early after EBV infection are usually lymphoproliferative processes in which latent virus infection in B cells is the principal cause of proliferation. Oral hairy leukoplakia may be the epithelial counterpart. In contrast, Burkitt’s lymphoma and nasopharyngeal carcinoma occur long after primary EBV infection; although etiologically related to EBV, viral gene expression may not be important to the growth of the clinically evident malignant cells.

Lymphoproliferative Disease

EBV is associated with B-cell lymphoproliferative disease in patients with congenital immunodeficiency. X-linked lymphoproliferative syndrome53 is an inherited immunodeficiency of males who have apparently normal cellular and humoral immune responses before infection with EBV. With EBV infection, most of the patients die of a fatal lymphoproliferative disorder or fulminant hepatitis, but some survive with hypogammaglobulinemia. EBV nuclear antigens have been detected in lesions from these patients. The gene mutated in X-linked lymphoproliferative syndrome has been identified as SAP,54 also termed SH2D1A or DSHP. SAP encodes an SH2-containing protein that interacts with the signaling lymphocyte-activation molecule (SLAM) to stimulate B and T cells.

EBV has also been associated with fatal infectious mononucleosis in persons with no known underlying genetic predisposition or in patients with congenital immunodeficiencies, such as severe combined immunodeficiency. EBV lymphoproliferative disease occurs in patients who are immunosuppressed due to transplantation or AIDS.55 EBV-seronegative patients who acquire infection after transplantation are at higher risk for the disease than those previously infected. Lymphoproliferative lesions are most commonly seen in the lymph nodes, liver, lungs, kidney, bone marrow, or small intestine. Tumors in transplant patients are usually classified as lymphomas or immunoblastic sarcomas; some patients have hyperplastic lesions. The proliferating lymphocytes in these tumors generally do not have chromosomal translocations.

AIDs-related lymphomas may be systemic (nodal or extranodal) lymphomas, primary-central nervous system lymphomas, or primary effusion lymphomas. The latter tumors often contain EBV in addition to HHV-8.

While most B-cell tumors in transplant recipients and central nervous system lymphomas in AIDS patients contain EBV, about 50% of other lymphomas in AIDS patients contain EBV. Tumors in patients with AIDS are usually either immunoblastic lymphomas or Burkitt’s lymphomas; the latter usually have c-myc translocations.

Tissues from transplant recipients or AIDS patients with EBV lymphoproliferative disease show expression of EBERs, EBNA-1, EBNA-2, and LMP-1 (Table 19.1).56 The expression of these EBV genes, which are targets for cytotoxic T cells, has important implications for therapy. Infusion of EBV-specific cytotoxic T cells or nonirradiated donor leukocytes has been effective in some cases for treatment of EBV lymphoproliferative disease.57,58

Table 19.1. Diseases Associated with EBV Latent Gene Expression.

Table 19.1

Diseases Associated with EBV Latent Gene Expression.

Burkitt’s Lymphoma

Seroepidemiologic studies show a strong association between Burkitt’s lymphoma and EBV in Africa. Over 90% of African Burkitt’s lymphomas are associated with EBV, while only about 20% of Burkitt’s lymphomas in the United States are associated with the virus. African patients with Burkitt’s lymphoma often have high levels of antibody to EBV antigens, and the virus can be recovered from the tissue. Burkitt’s lymphoma tissues express EBERs and EBNA-1, but not EBNA-2, EBNA-3, or LMP-1.59

Burkitt’s lymphomas contain chromosomal translocations that result in c-myc dysregulation. The most common chromosomal translocation is an 8/14 translocation, followed by an 8/22 translocation, both of which place a portion of the c-myc oncogene adjacent to an immunoglobulin gene. These translocations result in high constitutive expression of c-myc. Transgenic animals that overexpress c-myc in breast epithelial or B lymphoid cells develop monoclonal tumors.60 Dysregulated expression of c-myc in EBV-immortalized lymphoblastoid cell lines results in highly transformed cells that form tumors when injected into immunodeficient mice.61 These studies indicate that while c-myc is etiologically related to these tumors, dysregulated c-myc expression is not sufficient for malignancy.

EBV-associated endemic Burkitt’s lymphoma is thought to develop in steps. First, EBV infection may expand the pool of differentiating and proliferating B cells. Second, chronic holoendemic malaria may cause T-cell suppression and B-cell proliferation. Third, enhanced proliferation of differentiating B cells may favor the chance occurrence of a reciprocal c-myc (8/14 or 8/22) translocation placing c-myc partially under the control of immunoglobulin-related transcriptional enhancers, with development of a monoclonal tumor.

Nasopharyngeal Carcinoma

The nonkeratinizing nasopharyngeal carcinomas are uniformly associated with EBV. Seroepidemiologic studies indicate that patients with nasopharyngeal carcinoma have high levels of antibodies to EBV antigens. Patients usually have elevated levels of IgA antibody to the viral capsid antigen (VCA) and early antigen (EA). EBV antibody titers are useful in screening patients for early detection of nasopharyngeal carcinoma.62 Nasopharyngeal carcinoma tissue contains EBV genomes in every cell. Biopsy tissue shows expression of EBERs, EBNA-1, LMP-1, and LMP-2.9,63 These tumors are monoclonal with regard to EBV infection, indicating that EBV infection precedes malignant cell outgrowth at the cellular level. Unlike Burkitt’s lymphoma, the association of EBV with nasopharyngeal carcinoma is uniform and universal.

Hodgkin’s Disease

Patients with Hodgkin’s disease generally have higher titers of antibody to EBV VCA than the general population. Tissues from about 40 to 60% of patients with Hodgkin’s disease have EBV genomes. Cases of Hodgkin’s disease from developing countries are more likely to contain EBV genomes (> 90% of cases in some studies) than cases from the developed countries.64 The EBV genome is present in Reed-Sternberg cells. EBV is more often associated with aggressive subtypes (especially mixed cellularity) of Hodgkin’s disease. Reed-Sternberg cells from tumors express EBERs, EBNA-1, LMP-1, and LMP2, but not EBNA-2.65 Infusion of cytotoxic T cells generated from three patients with Hodgkin’s disease resulted in reduced symptoms and lower levels of EBV DNA in two patients.66

Other Tumors Associated with Epstein-Barr Virus

EBV genomes have been detected in patients with T-cell lymphomas present with fever, pneumonia, and numerous hematologic abnormalities. EBNA-1, LMP-1, and LMP-2 are expressed in peripheral T-cell lymphomas; however, EBNA-2 is not present.67 EBV DNA has also been detected in central nervous system lymphomas from patients with no underlying immunodeficiency, T cells in patients with virus-associated hemophagocytic syndrome, nasal T-cell lymphoma, carcinoma of the palatine tonsil, supraglottic laryngeal carcinoma, and angioimmunoblastic lymphadenopathy. EBV DNA and nuclear antigens have been detected in thymic carcinomas and in T-cell lymphomas from patients with lethal midline granuloma.

EBV DNA has been found in leiomyosarcomas in AIDS patients,68 and viral RNA and EBNA-2 have been detected in smooth muscle tumors in organ transplant recipients.69 EBV DNA, RNA, and EBNA-1 (but not EBNA-2 or LMP-1) have been detected in 7% of primary gastric carcinomas, especially in undifferentiated lymphoepithelioma-like carcinomas.

Human Herpesvirus 8 and Malignancies

In 1994, Chang et al. detected sequences of a new human herpesvirus in Kaposi’s sarcoma tissues from patients with AIDS.70 This agent is now termed human herpesvirus 8 (HHV-8) or Kaposi’s sarcoma–associated herpesvirus. HHV-8 has been found in nearly all biopsies of classic Kaposi’s sarcoma, African endemic Kaposi’s sarcoma, Kaposi’s sarcoma in HIV-seronegative transplant recipients and homosexual men, and Kaposi’s sarcoma in patients with AIDS.71 HHV-8 is present in the endothelial and spindle cells of the tumor but not in normal endothelium.72 Most of the tumor cells are latently infected with the virus, but 1 to 5% of the spindle cells in HIV-positive Kaposi’s sarcoma show lytic HHV-8 infection. Some studies indicate that Kaposi’s sarcoma is a monoclonal tumor,73 while others indicate that it is a polyclonal process. HHV-8 is also present in the peripheral blood mononuclear cells of about 50% of patients with Kaposi’s sarcoma and its presence is predictive of development of the malignancy.74 HHV-8 has also been detected in the saliva of patients with Kaposi’s sarcoma, and infrequently in semen.

HHV-8 has also been found in primary effusion lymphomas in patients with AIDS.72,75 These body cavity–based lymphomas of B-cell lineage are located in the pleural, peritoneal, or pericardial space and usually contain EBV genomes as well as HHV-8. Some HHV-8–positive lymphomas have been found in patients without AIDS.

HHV-8 has also been detected in biopsies from some patients with multicentric Castleman’s disease, especially in the variant known as the plasma cell type.72,76 HHV-8 is detected more frequently in biopsies from HIV-positive patients than in those without HIV. This disease presents as generalized lymphadenopathy, fever, and hypergammaglobulinemia. HHV-8 is present in the immunoblastic B cells of the mantle zone of the lesions.

While some reports indicate that HHV-8 sequences are present in dendritic cells from patients with multiple myeloma,77 other studies have failed to detect HHV-8 DNA and proteins in these lesions or antibodies to the virus in patients with myeloma.72,78 While HHV-8 RNA has been detected in some prostatic carcinomas, other studies have not detected viral proteins in these tumors or an increased incidence of antibodies to the virus in patients with prostate carcinoma.72,78 HHV-8 has been detected in a variety of other tumors including angioimmunoblastic lymphadenopathy with dysproteinemia and angiosarcoma, but detection of the virus has not been consistent among various studies.

Epidemiology

The seroprevalence rates for HHV-8 vary from < 5% in normal blood donors in the United States or United Kingdom to 30 to 35% in HIV-positive homosexual men.74,79,80 Antibody to HHV-8 is more common in African and Mediterranean populations. At least 85% of patients with Kaposi’s sarcoma have antibodies to HHV-8.81 The prevalence of Kaposi’s sarcoma is lower in women than in men, and HIV-seropositive women have a much lower incidence of antibody to HHV-8 than seropositive men. HHV-8 seropositivity in HIV-positive homosexual men is predictive of subsequent development of Kaposi’s sarcoma.79 The virus is not thought to be pathogenic in most healthy individuals; however, in immunocompromised persons, it is strongly associated with Kaposi’s sarcoma. Thus, while infection with HHV-8 appears to be required for development of Kaposi’s sarcoma, it is probably not sufficient and other cofactors, such as HIV and immunosuppression, may have important roles.

HHV-8 is thought to be sexually transmitted in homosexual men,74 but may occasionally be transmitted vertically from mother to child. HHV-8 has been transmitted by renal allografts, and two kidney transplant recipients have subsequently developed Kaposi’s sarcoma.82

Human Herpesvirus 8 Gene Products

The complete sequence of HHV-8 was determined in 1996, and the virus is approximately 165 kilobases in length.83 Sequence analysis indicates that HHV-8, like EBV, is a member of the gammaherpesvirus subfamily. However, while EBV is a lymphocryptovirus (gamma-1-herpesvirus), HHV-8 is a rhadinovirus (gamma-2-herpesvirus). Cell lines derived from primary effusion lymphomas maintain HHV-8 in a latent state and can be induced to undergo lytic virus replication by the addition of phorbol ester (TPA) or butyrate.84 HHV-8 encodes a large number of cellular homologues (Table 19.2) that have been grouped into different classes, depending on when they are expressed in primary effusion lymphoma cell lines.85

Table 19.2. Selected HHV-8 Genes and their Cellular Homologues and Activities.

Table 19.2

Selected HHV-8 Genes and their Cellular Homologues and Activities.

A practical system for transmitting HHV-8 to uninfected cells with amplification of virus has not yet been developed. Foscarnet, ganciclovir, and cidofovir, but not acyclovir, inhibit virus production when primary effusion lymphoma cell lines are induced to replicate virus.86 Moreover, foscarnet and ganciclovir have been reported to reduce the frequency of Kaposi’s sarcoma lesions in some, but not all, studies.87,87a

Infection of primary human endothelial cells with HHV-8 results in transformation with anchorage-independent growth and induction of telomerase activity.88 Surprisingly, the virus is present in only a small proportion of these cells and the proliferation and increased survival of the infected cells is probably due to a paracrine mechanism.

Several HHV-8 genes may contribute to its oncogenicity. Expression of the HHV-8 K1 gene in rodent fibroblasts results in transformation of the cells.89 Substitution of the STP oncogene in Herpesvirus saimiri with the HHV-8 K1 gene maintains the transforming activity of Herpesvirus saimiri in vitro and in vivo. The cytoplasmic domain of the K1 protein has an immunoreceptor tyrosine-based activation motif (ITAM), and the protein induces tyrosine phosphorylation in cells.90 Expression of this gene in cells results in constitutive calcium-dependent signal transduction in B cells in the absence of exogenous stimuli.91

The HHV-8 K2 gene encodes an interleukin (IL)-6 homologue, which is expressed in cells from primary effusion lymphomas and Castleman’s disease but is absent or expressed at very low levels in Kaposi’s sarcoma. Since IL-6 is a B cell growth factor it may act as an autocrine growth factor for lymphoid tumors. HHV-8 IL-6 prevents death of IL-6–dependent B9 cells in vitro.92 The HHV-8 K4 and K6 genes encode two chemokines — the viral macrophage inflammatory proteins (MIP)-I and -II. MIP-I inhibits replication of HIV strains dependent on CCR5.92 MIP-I and MIP-II partially block HIV infection of peripheral blood mononuclear cells and are angiogenic in a chorioallantoic membrane assay. MIP-II is a chemoattractant for eosinophils.93 MIP-II binds to both CC and CXC chemokines and blocks calcium mobilization induced by chemokines.94

The HHV-8 K9 gene encodes a homologue of the cellular interferon regulatory factor (IRF). K9, known as vIRF, transforms NIH 3T3 cells, induces tumors in nude mice, and represses transcriptional activation induced by interferon-alpha, -beta, and -gamma.95 The HHV-8 K12 gene is expressed in Kaposi’s sarcoma tissue and primary effusion lymphomas. K12, referred to as kaposin, induces transformation of cells, and injection of these cells into nude mice results in highly vascularized sarcomas.96

HHV-8 ORF16 encodes a homologue of the cellular Bcl-2 protein. HHV-8 Bcl-2 is expressed in primary effusion lymphoma cells and Kaposi’s sarcoma lesions and inhibits apoptosis.97 The ORF71 gene encodes a homologue of cellular FLIP (FLICE inhibitory protein) that blocks apoptosis. HHV-8 ORF71 has been shown to block apoptosis in mouse cells and promote tumor growth.97a

HHV-8 ORF72 encodes a cyclin D homologue that is expressed in primary effusion lymphomas and in spindle cells of Kaposi’s sarcoma lesions. The viral cyclin binds to and activates cdk6, and stimulates cell-cycle progression in normally quiescent fibroblasts.98 ORF72 phosphorylates and thereby inactivates the retinoblastoma tumor suppressor protein.99

HHV-8 ORF73 is the latency-associated nuclear antigen and is expressed in Kaposi’s sarcoma tissues and primary effusion lymphomas. This protein localizes with HHV-8 DNA episomes and is required for persistence of the episome in cells.100

HHV-8 ORF74 encodes a G protein–coupled receptor that is homologous to the cellular IL-8 receptor; however, unlike the latter protein, the HHV-8 receptor is constitutively active and induces cellular proliferation.101 This protein has been shown to activate angiogenesis102 and is expressed in Kaposi’s sarcoma and primary effusion lymphoma cells. A spliced gene located between ORF75 and the terminal repeats of the genome encodes a membrane protein that, like EBV LMP-1, interacts with TRAFs 1,2, and 3.103 Recently, viruses homologous to HHV-8 have been identified in macaque monkeys.104,105

Oncogenic Potential of Other Human Herpesviruses

Cytomegalovirus has not been shown to be oncogenic in humans. While viral antigen or viral DNA has been demonstrated in some tumors (e.g., Kaposi’s sarcoma in AIDS patients, colon carcinomas), a similar level of cytomegalovirus antigen or DNA indicative of latent infection, has been detected in nontumor tissue from control patients. Similarly, initial seroepidemiologic studies suggested a role for herpes simplex virus 2 in cervical carcinoma, yet there has been no convincing evidence for viral DNA or antigen in these tissues. Finally, although human herpesvirus 6 DNA has been detected in some lymphomas, it is unknown whether the virus is involved in the pathogenesis of these tumors or, whether the virus is associated with the non-neoplastic lymphocytes.

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