Transactivation and expression of cellular and viral genes

RAG1, RAG2, CD21, CD23, c-fgr, cyclin D2, LMP1, LMP2A, LMP2B

LFA1, LFA3, HLAII, ICAM1, blc-2, vimentin

Chromosome translocations t(8;14), t(2;8), t(8;22)

Increased expression of the oncogene c-myc, directed by the promoter-enhancer of the immunoglobulin genes nocarcinomas.28,31,32 EBV is present in clonal, episomal form in the malignant epithelial cells that express EBNA1 but not other EBNA genes or LMP1.28,30-32 Recently, it was shown that the EBV BARF1 gene, which acts as an oncogene,33 is expressed in EBV-positive gastric adenocarcinomas,32,34 suggesting that BARF1 contributes to gastric cancer. Leiomyomas and leiomyosarcomas are rare smooth muscle cell tumors whose frequency is increased in immunocompromised patients, especially in HIV-positive patients and in organ transplant recipients.35,36 Leiomyomas and leiomyosarcomas developing in immunocompromised patients, but not in immunocompetent individuals, are associated with EBV, and the tumor cells harbor episomal monoclonal EBV genomes.35 EBV is the likely cause of oral hairy leukoplakia,28 an EBV cytolytic lesion not known, and is associated with undifferentiated parotid carcinoma.37 The possible association of EBV with some aggressive forms of breast cancer has been suggested by some investigators,38 but presently the weight of evidence does not support a pathogenic role of EBV in breast cancer. The mechanisms of cellular transformation by EBV are reported in Table 17.2. LMP-1 also induces a variety of inva-siveness, metastasis, and angiogenic factors including matrix metalloproteinase (MMP)-9, cyclooxygenase (COX)-2, vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF)-2, and HIFIX.

Human Herpesvirus 8

Human herpesvirus 8 (HHV-8) is a herpesvirus recently isolated from Kaposi's sarcoma (KS) tissue39 using the technique of representational difference analysis.40 HHV-8 is a gamma-herpesvirus, showing sequence homology to EBV and to herpesvirus saimiri, a squirrel monkey virus that induces lymphoproliferative disorders in monkeys and transforms human T cells.41 HHV-8 is associated with KS, primary effusion lymphoma (PEL), and Castleman's disease. PELs are AIDS-associated lymphomas characterized by malignant lymphocyte effusions in the pleural, pericardial, and peritoneal cavities, usually without significant tumor masses or lymphadenopathy. All PELs contain HHV-8 DNA and most, but not all, are coinfected by EBV,42-44 suggesting that the two viruses may cooperate in neoplastic transformation. Multicentric Castleman's disease (MCD) is a rare polyclonal lymphoproliferative disorder45 appearing in both immuno-compromised and immunocompetent individuals. HHV-8 is present in nearly 100% of HIV-1-positive patients with MCD. Among MCD immunocompetent patients, HHV-8 is detected in about 40% of cases.44

KS occurs in four epidemiologic forms46: (1) classic KS, a rare tumor of elderly men, usually of Mediterranean origin, with a mild clinical course; (2) endemic KS, developing in HIV-1-negative individuals in equatorial Africa; (3) iatrogenic KS, occurring in immunosuppressed transplant recipients; and (4) epidemic KS, presently the most common form of KS, developing in patients with AIDS. KS lesions exhibit a complex morphology and contain a variety of cell types, including malignant spindle cells, probably of endothelial origin.47-49 KS cells release various lymphokines, including IL-6 genome, interferon-g (IFN-g), basic fibroblast growth factor (bFGF), tumor necrosis factor-g (TNF-g), and VEGF. KS growth is enhanced by inflammatory cytokines of the Th1 type and by the HIV-1 Tat protein.47 These observations suggest that the local dysregulation of cytokines plays an important role in the development of KS lesions. HHV-8 DNA was detected in 89% to 100% of KS biopsies and in only 2% of non-KS biopsies, except for blood (8%-25%), from the same individ-ual,43,44 indicating that the viral load is highest in KS lesions. Seroepidemiology demonstrates that HHV-8 antibody prevalence is low (2%-3%) in the United States and in England, and that it is greater and increases steadily with age in Mediterranean Europe and in Africa. HHV-8 seroprevalence reaches 85% in KS patients and 35% in homosexual men. Moreover, in this latter category the prevalence of HHV-8 antibodies rises with the increasing number of homosexual partners in the previous 2 years,44 suggesting that HHV-8 could be the sexually transmitted agent previously suggested to be associated with KS.48,49 HHV-8 is not present in other vascular tumors, including angiomas, hemangiomas, and angiosarcomas, and is only rarely detected in other forms of skin tumors, such as squamous cell carcinomas and melanomas.44 The presence of HHV-8 DNA in peripheral blood cells of HIV-1-positive individuals and HHV-8 reactivation from a latency stage correlates with a greater risk of developing KS.44,50,51 PCR in situ hybridization, RNA in situ hybridization, and immunohistochemistry showed HHV-8 in nearly all spindle cells of KS lesions.44,51,52

The oncogenic mechanisms of HHV-8 are not fully understood. Sequence analysis of the viral genome53 yielded clues to the transforming activity of HHV-8.44,52,50 Several HHV-8 genes have significant sequence homology to human genes,44,50,52,54 suggesting that the virus has captured cellular genes during evolution. The viral homologues are similar to cellular genes involved in apoptosis, growth control, cell-cycle regulation, and chemokine and cytokine signaling. HHV-8 contains a gene homologous to bcl-2 that inhibits apoptosis.55 The viral antiapoptotic activity is supported by two other cellular homologues: FLIP, which interferes with apoptosis signaled through the FLICE death; and LANA, which binds p53, inhibiting p53-mediated apoptosis.44,50,52 HHV-8 also codes for a cyclin D-like gene whose protein product participates in pRb phosphorylation.56,57 Another HHV-8 protein that is involved in cell proliferation is the G protein-coupled receptor (GPCR), which is constitutively active for downstream signaling in the absence of the chemokine ligands.58 GPCR shows a high sequence homology to the cellular IL-8 receptor, transforms NIH3T3 mouse fibroblasts in vitro, and induces VEGF expression.59 Transgenic mice expressing HHV-8 GPCR in hematopoietic cells develop angioproliferative KS-like lesions in multiple organs.60 The viral MIP-I, MIP-II, and MIP-III proteins exhibit homology to the cellular chemokine MIP-1-a. MIP-I and MIP-II possess strong angiogenic potential and may therefore contribute to the marked vascularization characteristic of KS.61 The K1 protein of KSHV, the homologue of EBV LMP-1, also induces MMP-9 and VEGF expression (John Pagano, personal communication). Furthermore, the virus encodes a homologue of cellular IL-6, a possible growth factor for KS cells, and up to four proteins related to cellular interferon-reg-ulatory factors (IRF)52,54,62 that may confer resistance to the antiproliferative effects of IFN-a. Because KS growth appears to be supported by a variety of cytokines,47 it is interesting that HHV-8 codes for homologues of cellular cytokines and cytokine receptors that may function as growth factors for the proliferation of KS cells. HHV-8 has also been linked to the development of multiple myeloma,63 but this association is not established.

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