Kaposi's sarcoma associated herpesvirus (KSHV) has been linked to the development of Kaposi's sarcoma (KS), primary effusion lymphoma (PEL) and a proportion of Castelman's disease. We have been interested in elucidating the pathogenetic mechanisms underlying KSHV-associated diseases and exploring stratetegies for treatment. The KSHV encoded cytokine vIL-6 has been a focus of our studies. It is produced predominantly during viral replication and exhibits approximately 25% amino acids identity to human and mouse IL-6, suggesting that it may be the result of viral piracy of a useful cellular gene. Through experiments in vitro and in vivo, we have characterized the vIL-6 receptor and described the biological activities of vIL-6. In particular, mice inoculated with vIL-6 display increased hematopoiesis in the myeloid, erythroid, and magakaryocytic lineages; plasmacytosis in the spleen and lymph nodes; hepatosplenomegaly, and polyclonal hypergammaglobulinemia. Over-expression of vIL-6 in mice is tumorigenic, in part due to vIL-6 induction of vascular endothelial growth factor (VEGF). Neutralizing antibodies directed at VEGF prevent the development of PEL that is KSHV infected and produces vIL-6. Using newly generated monoclonal antibodies against vIL-6 and a sensitive vIL-6 ELISA developed with these antibodies, we have measured serum vIL-6 levels in KSHV-associated diseases, and correlated circulating vIL-6 levels with disease progression and response to therapy. gp130 serves as the vIL-6 receptor. Signaling through gp130 promotes STAT3 phosphorylation. PEL cells express a constitutively active STAT3. PEL cells transfected with a dominant negative form of STAT3 or treated with the STAT3 inhibitor AG490 rapidly die by apoptosis associated with diminished expression of the anti-apoptotic protein Survivin. Over-expression of Survivin in PEL cells renders them resistant to apoptosis induced by STAT3 inhibition. Thus, through the expression of cytokines, KSHV can promote STAT3 phosphorylation and expression of the anti-apoptotic protein Survivin ensuring extended survival of the virally infected cells. The linkage between STAT3 activation and Survivin expression may be useful in the design of new therapeutic approaches for the treatment of KSHV-associated and other malignancies.
