) The Kaposi's sarcoma-associated herpesvirus (KS or human herpesvirus 8 (HHV 8) is consistently present in Kaposi's sarcoma and primary effusion (body cavity-based) lymphoma, two malignancies frequently found in patients with AIDS. The applicant has identified and sequenced two genes within this virus that appear to represent viral oncogenes since they encode proteins homologous with cellular proteins that are involved in cell cycle control. These genes encode a G protein-coupled receptor (GCR) and a cyclin D homolog, respectively. Both genes are expressed at the RNA level in Kaposi's sarcoma and primary effusion lymphoma. The principal objective of the studies proposed is to characterize the KSHV GCR and cyclin proteins structurally and functionally in order to assess their role in oncogenesis. The first specific aim is to analyze the pattern of protein expression and regulation of both the KSHV GCR and cyclin in KSHV-positive tissues and cell lines using antibodies prepared against the purified proteins. The clinical usefulness of these antibodies in the histologic diagnosis of the various KSHV-associated diseases will be evaluated. The second specific aim of this application is to characterize the KSHV GCR functionally by confirming preliminary evidence that interleukin 8 is a ligand for this receptor and determining whether an autocrine loop or paracrine loop and/or constitutive receptor activation are mechanisms involved in KSHV-mediated transformation. The applicant will also characterize the subsequent pathways involved in signal transduction by the KSHV GCR. The third specific aim is to analyze the role of the KSHV cyclin in cell cycle progression. The study will determine which cyclin-dependent kinases are associated with this viral cyclin and whether this association leads to protein kinase activity resulting in Rb protein phosphorylation. The regulation of these complexes by cyclin-dependent kinase inhibitors, including pl6 (INK4a), p2l and p27 (Kip1), will be evaluated. These experiments will lead to a better understanding of the mechanisms employed by KSHV in the development of Kaposi's sarcoma and malignant lymphoma, the two malignancies most frequently associated with HIV infection, and will contribute to the general knowledge of human oncogenic viruses.
Showing the most recent 10 out of 11 publications
