HHV-8 AND KAPOSI'S SARCOMA

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Kaposi's sarcoma [KS] is a tumor-like lesion that occurs in a variety of settings, including in elderly men of certain ethnic backgrounds, renal transplant patients, residents of parts of Africa, and HIV-1 infected people. In the latter setting, it follows a far more aggressive course than in the absence of HIV-1. A recently identified human herpesvirus, called KS herpesvirus [KSHV] or human herpesvirus type 8 [HHV8], is prevalent in all forms of KS, suggesting that it is a necessary etiologic factor for KS. It is not clear whether KS is a tumor or merely a hyperplasia. HS lesions have a complex cellular makeup that includes macrophages, lymphocytes, and cells with a spindle morphology, which are thought to be the abnormal cell. The origin of spindle cells is not clear, and they may originate from more than one linage. Virtually all spindle cells, however, contain HHV-8, as shown by in situ hybridization, further suggesting that HHV-8 plays a role in KS. KS lesions are rich in inflammatory cytokines, and the development of KS appears in part to be drive by abnormal expression of cytokines and growth factors. We and others have shown that HHV-8 codes for structural and functional homologs of several cytokine, chemokine and chemokine receptor genes. It is the purpose of this project to explore the relationships of the viral and cellular cytokines and chemokines to virus replication and KS pathogenesis. Specifically, the effects of IL-1beta, IL-6, TNF-alpha, IFN- gamma and oncostatin M on HHV-8 replication and gene expression will be determined. Where such effects are observed, the mechanisms of activation of repression by the host cytokines will be determined. Expression of viral cytokine/chemokine genes [vIL-6, vMIP-1A and -B and ORF74] in KS will be characterized by RT-PCR, immunohistochemistry and serology. Functional aspects of these viral genes will be analyzed by expression in vitro and in transgenic mice. This will include their influence on the growth of KS lesions in mouse model systems. Results from these studies will provide important information on the roles of host and viral cytokines and chemokines on HHV-8 expression and KS pathogenesis.