ROLE OF VIL-6 IN PRIMARY EFFUSION LYMPHOMAS

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Human herpesvirus-8 (HHV-8) is a recently discovered virus, sequences of which have been found consistently in Kaposi's sarcoma of all types (AIDS-associated, classical, endemic), in AIDS-associated primary effusion lymphoma (PEL), and at high frequency in lesions of multicentric Castleman's disease (MCD). Recent reports indicate that HHV-8 may also be associated with multiple myeloma (MM). It has been proposed that HHV-8 is directly or indirectly involved in the development and progression of these diseases. Of relevance are findings that implicate cytokines, particularly IL-6, in the development of KS, PEL, MCD and MM; IL-6 promotes the growth of KS, PEL and myeloma cells and is found at elevated levels in MCD lesions and patient sera. Prior to complete sequencing of the viral genome, partial sequence analysis determined that HHV-8 is a member of the gamma- herpesvirus subfamily and that of the herpesviruses for which sequence data are available it is most closely related to herpesvirus saimiri (HVS). On the basis of presumed general genetic collinearity between the genomes of HHV-8 and HVS, we identified a gamma-herpesvirus-divergent genomic locus in HHV-8 that encodes a homologue of interleukin-6 (vIL-6) and three beta- chemokine homologues (vMIP-1A, vMIP-1B, BCK), two of which are closely related to macrophage inflammatory protein-1. We hypothesize that HHV-8 could effect disease pathology with which the virus has been associated by direct mitogenic stimulation of HHV-8 infected or surrounding cells by vIL-6 and by cytokines secreted by lymphocytes recruited into infected tissues through the chemotactic properties of the v-chemokines. The focus of this proposal is to determine the effects and mechanisms of action of vIL-6 on PEL cell growth and signal transduction. The specific aims are (1) to determine the effects of exogenously added vIL-6 on PEL cell growth and survival and the influence of IL-6R on these activities; (2) to identify VEGF species and mitogenic/anti-apoptotic functions induced by vIL-6 in PEL cells; (3) to identify the signal transduction pathways, Jak/STAT and/or MAPK, and MAPK pathway intermediates that are activated in PEL cells in response to vIL-6 and determine the role of IL-6R in pathway selection; (4) to undertake in vitro vIL-6-receptor binding assays using wild-type and specifically altered forms of gp130 and IL-6R to characterize the nature of and requirements for vIL-6-gp130/IL-6R associations. These combined studies will provide data that determine the relative contributions of hIL-6 and vIL-6 to PEL cell growth, identify intracellular pathways through which the effects of vIL-6 are mediated in PEL cells, and determine the characteristics of functional vIL-6 associations with gp130 and IL-6R. The generated data will provide the basis for the design of potentially therapeutic strategies to specifically block vIL-6 mitogenic functions with respect PEL and other HHV-8 associated diseases.