Host cell responses to viral infection include shut-down of the cell cycle, induction of apoptosis and induction of cell-mediated immunity by increased MHC presentation. Some viruses, such as adenoviruses and papillomaviruses, have developed effective mechanisms to escape these defenses. Successful abrogation of these pathways by a virus may contribute to tumor development through dysregulation of cell replication, cell immortalization and escape from immune surveillance. Kaposi's sarcoma, the most common AIDS-related malignancy, is associated with KSHV/HHV8 infection. The KSHV genome has recently been sequenced and found to encode homologues to four cytokines or cytokine-signal transduction proteins. Two of these proteins, viral IL6 (vIL6) and viral interferon regulatory factor (vIRF), are likely to interfere with host cell defenses to infection. Both proteins are functional and expressed during latent and lytic KSHV replication in cell lines derived from primary effusion lymphomas. The vIL6 can prevent apoptosis of IL6-dependent mouse myeloma cells and is expressed primarily in infected hematopoietic tissues. The KSHV vIRF is oncogenic in nude mice and may inhibit interferon-induced gene transcription. This is the first direct evidence that KSHV is a DNA tumor virus and suggests that vIRF may interfere with immunity induced by interferon. This application seeks to characterize the potential role of IL6 and vIRF in the pathogenesis of Kaposi's sarcoma and KSHV-related disorders. The activity of vIL6 in preventing apoptosis will be examined as it related to lymphocyte immortalization and as an autocrine factor for KSHV-infected cell lines. Examination of KSHV-infected tissues for vIRF expression will determine whether or not this protein is capable of playing a role on KSHV pathogenesis. The effect of vIRF on modifying expression of IFN-stimulated genes involved in immune surveillance and tumor suppression also will be examined, and its capacity to serve as an oncogene in transforming cells will be explored. Mice transgenic for vIL6 and for vIRF will be generated to serve as animal models for KSHV-related diseases and to examine the in vivo effects of viral gene expression on immunity and on spontaneous tumor development. These studies will define the actions of these cytokine signaling proteins and may lead to fundamental discoveries on the mechanisms of AIDS-related neoplasia.
