Viral G Protein–Coupled Receptor and Kaposi's Sarcoma

The most recently identified human herpesvirus, Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) or human her-pesvirus 8 (HHV-8), has been found to be a necessary, although perhaps not sufficient, etiologic agent for all forms of KS (1, 2). This virus is also invariably present in a rare subset of malignant lymphomas, primary effusion lympho-mas (PELs), and in a significant percentage of patients with multicentric Castleman's disease, an angiolymphoprolifera-tive disorder (3, 4). Both KS and PEL occur more frequently, but not exclusively, in HIV-infected individuals, and all cases of HIV-related multicentric Castleman's disease are infected with KSHV. These findings suggest an important role of immunosuppression and HIV infection in KSHV-mediated pathogenesis. Although it remains controversial whether KS is a malignant neoplasm, KS lesions probably evolve from a reactive, inflammatory/angioproliferative process into true clonal cancers. Thus, KS is generally considered a malig-nancy, especially because of its frequent multifocal and aggressive behavior. Given the definitive association of KSHV with two different human malignancies, it is not difficult to consider KSHV to be a human oncogenic virus. KSHV is a gammaherpesvirus that is homologous to EBV and herpesvirus saimiri (HVS), human and simian viruses , respectively, that are able to transform lymphoid cells in culture and cause malignant lymphomas in some circumstances. Genomic sequencing has revealed that KSHV contains several genes with likely oncogenesis-related functions that subvert pathways involved in cellular activation, proliferation, differentiation, and survival. Many of these genes are viral homologues of cellular genes, including those encoding viral cyclin D, IFN regulatory factors (IRFs), viral IL-6 (vIL-6), BCL-2, FLICE-inhibitory protein (FLIP), three chemokines (viral macrophage inflam-matory protein [vMIP]-I,-II, and-III) and last, but not least, a G protein–coupled receptor (KSHV GPCR). Three of these genes have been found to be transforming in mouse fibroblast assays (vIRF, KSHV GPCR, and vIL-6), and two are homologous to cellular oncogenes (vBCL-2 and v-cyclin D). Two additional viral genes having no direct cellular counterpart, those encoded by open reading frame K1 (containing an immunoreceptor tyrosine-based activation motif [ITAM]) and K12, have also been found to be transforming in certain experimental assays. Therefore, KSHV qualifies as the virus with the most putative oncogenes identified to date. Thus, the following dilemma: why are KSHV-associated neoplasms so rare in the general population in spite of a seroprevalence of KSHV infections of at least 5% in Western countries? Why is KSHV only poorly transforming after infecting cells in culture? This may be partially …