Signaling activities of gammaherpesvirus membrane proteins.

Members of the Herpesviridae family have large doublestranded DNA genomes and replicate in the nucleus of the host cell. Based on genomic organization and biological characteristics, herpesviruses are classified into three subfamilies: alpha, beta, and gamma (Fig. 1A). The gammaherpesviruses replicate and persist in lymphoid cells, but some are capable of undergoing lytic replication in epithelial or fibroblast cells. These viruses can be subdivided into two genera: lymphocryptoviruses (gamma-1) and rhadinoviruses (gamma-2) (Fig. 1A). The lymphocryptoviruses (gamma-1) include Epstein-Barr virus (EBV) or Human herpesvirus 4, Lymphocryptovirus of rhesus monkeys, and Herpesvirus papio of baboons, whereas the rhadinoviruses (gamma-2) include Herpesvirus saimiri (HVS), Kaposi’s sarcoma-associated herpesvirus (KSHV) or Human herpesvirus 8, Rhesus monkey rhadinovirus (RRV), Equine herpesvirus 2, and Mouse herpesvirus 68 (Fig. 1B). The gammaherpesviruses, including HVS, EBV, KSHV, and RRV, are capable of establishing latent infection in lymphocytes. Both HVS and EBV have also been shown to transform lymphoid cells and to induce lymphoproliferative diseases in the natural or experimental host. EBV has been shown to be associated with several diseases in humans (16, 40, 78). These include infectious mononucleosis (IM), Burkitt’s lymphoma (BL), nasopharyngeal carcinoma (NPC), Hodgkin’s disease (HD), and T-cell lymphomas (1, 11, 65, 83, 84, 95, 96, 108, 116, 141). Primary EBV infection is usually asymptomatic, but a proportion of EBV-infected individuals develop IM, a disease characterized by lymphadenopathy and fatigue, later in life. A rare disease called fatal IM or X-linked lymphoproliferative (XLP) syndrome is an EBV-dependent malignancy characterized by uncontrolled immunoblastic lymphomas which are consistently EBV positive (115). The genetic defect in XLP is in the SLAM-associated protein, SAP. The mutated SAP protein in XLP patients affects T/B-cell interactions induced by SLAM, leading to an inability to control the B-cell proliferation caused by EBV infections (123, 133). BL is a malignancy that principally affects children, especially those that live in regions of Africa with a high incidence of malaria (16). The tumor cells of these lymphomas are closely associated with EBV, with 100% of the lymphomas scoring positive for EBV. In other areas of the world, however, the occurrence of BL is more sporadic and a lower percentage of these lymphomas are EBV positive (65). BL is characterized by distinct chromosomal translocations of the c-myc oncogene and immunoglobulin promoter sequences, resulting in the deregulation of c-myc expression (23). Another EBV-associated disease is NPC, a malignancy of the squamous epithelium situated in the nasopharynx (117). EBV is consistently present in cases of epithelial dysplasia, and it is thought to have arisen from clonal expansion of latently infected cells (113, 116). The incidence of NPC is high in Southern China, Northern Africa, and Eskimo populations. HD is the most common malignancy in the Western world, with about 30 to 90% of all HD lymphomas being EBV positive. Like NPC, the EBV genomes in these tumor cells are monoclonal (139). EBV is also present in about 70% of all immunoblastic lymphomas in human immunodeficiency virus (HIV)-infected individuals and in 100% of immunoblastic lymphomas of immune-suppressed posttransplant patients. Recently, EBV, a primarily B-cell-tropic virus, has been detected in different types of human T-cell lymphomas. About 100% of all nasal T-cell lymphomas in Southeast Asia and 100% of T-cell tumors in XLP males contain EBV (65). Epidemiological studies from many laboratories, using antibody prevalence assays, PCR, and immunohistochemistry, suggest that KSHV is the etiologic agent responsible for Kaposi’s sarcoma (KS). KSHV DNA sequences have been widely identified in KS tumors from HIV-positive and HIV-negative patients (20, 93, 132). KSHV has also consistently been found in specific lymphoproliferative diseases such as body cavity-based lymphomas (BCBLs), also called pleural effusion lymphomas, and lymphoblastic variants of multicentric Castleman’s disease (MCD) (17, 46, 102, 112, 130). These are principally or exclusively of B-cell origin. There are reasons to believe that the abnormal cell proliferation in KS may differ from the traditional virus-transformed cell paradigms of other transforming viruses. The KS lesion has a mixed cell phenotype. One unusual cell consistently present, and thought to be critical, is a spindle-shaped cell believed to be of endothelial origin. While cells cultured from KS lesions do not contain KSHV, spindle cells in the KS lesion do contain KSHV genetic information. Several studies have suggested a high level of cytokines and chemokines within KS lesions and a dependence on these cytokines and chemokines for maintenance of the lesion (20, 106). BCBLs were first identified in patients with AIDS and were later found to have a high incidence of EBV and KSHV coinfection, although some lymphomas were only positive for KSHV (17, 69). BCBLs are thought to be monoclonal in origin and lack many B-lymphocyte antigens like CD19, CD20, and cell homing and adhesion markers (13, 34). MCD is an atypical lymphoproliferative disorder that includes hyperplasia, lymphadenopathy, and splenomegaly. Both HIV-infected and -uninfected individuals develop MCD, although there is a high rate of KSHV infection in the lymph nodes of HIV patients with MCD (18, 66, 130). It has been demonstrated that viral interleukin-6 (IL-6) acts as an autocrine or paracrine factor in the lymphoproliferative processes common to both BCBLs and MCD (111, 131). In addition, KSHV has been shown to im* Corresponding author. Mailing address: Department of Microbiology and Molecular Genetics, New England Regional Primate Research Center, Harvard Medical School, One Pine Hill Dr., Box 9102, Southborough, MA 01772-9102. Phone: (508) 624-8083. Fax: (508) 786-1416. E-mail: [email protected].