Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8) is consistently present in primary effusion lymphomas (PELs). The specificity of this association suggests that KSHV plays an important role in the pathobiology of this lymphoid malignancy occurring more frequently in HIV-infected individuals. We were the first to describe this association, and to develop PEL cell lines, which are still the only efficient tool for viral propagation and isolation, and remain an important source of antigen for serologic assays. Our laboratory has also played a pivotol role in the understanding of the clinical, pathologic, and molecular characteristics of PELs. While much has been learned since the identification of KSHV in PELs, our understanding of this disease remains incomplete. We have collected and characterized a significant number of PEL specimens and cell lines, which will be used as a resource to assess the role of KSHV in the pathobiology of primary effusion lymphomas. KSHV contains multiple putative viral oncogenes, as they encode proteins that can affect cellular proliferation and survival. However, which of these are necessary for PEL development and maintenance remains completely unknown. Activation of the transcription factor NFkB is a likely target of KSHV infection, as it is a potent induced of genes involved in he proliferation and survival of lymphocytes, and an important target of the transforming genes of EBV and HLTV1. Our preliminary data indicates that NFkB is constitutively active in PEL cell lines and clinical samples, and its inhibition results in considerably decreased cellular survival. Therefore, we hypothesize that subversion of cellular signaling cascades by KSHV-encoded genes, and in particular activation of NFkB, is critical for KSHV lymphomagenesis. In addition, we hypothesize that among the KSHV-encoded proteins, vFLIP is responsible for most of the NF-kB activity observed in latently infected PEL cells, which will be tested in Specific Aim #1.
Specific Aim #2 is to analyze the activation of the MAP kinase signal transduction pathways in PEL cells. We will determine the consequences of signaling leading to NF-kB and MAP kinase activation in the proliferation, survival, and phenotypic characteristics of PEL cells (Specific Aim #3). These studies should contribute to our understanding of the molecular mechanisms that are critical in KSHV lymphomagenesis and increase our knowledge of the pathobiology of PEL, a highly aggressive and still incurable type of AIDS-related malignancy.
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