) A Kaposi's sarcoma associated herpes virus (KSHV), also known as human herpesvirus 8, has been postulated to play a pathogenetic role in Kaposi's sarcoma and body cavity-based lymphomas. The overall goal of this project is to analyze the T cell mediated immune response to KSHV among cohorts of HIV infected individuals, including KSHV infected (seropositive, lytically infected and seronegative latently infected) persons, in order to determine if the immune response influences tumor development and clinical course. Critical to the outcome of these studies are access to KSHV genes, which this group helped to clone, and KSHV specific probes that allow determination, by in situ hybridization of infected tissues, whether individuals have latent or lytic KSHV infection and a novel system for introducing viral proteins into antigen presenting cells that enhances the ability of these cells to elicit antigen specific T cell responses.
The specific aims are as follows: 1) perform in situ hybridization with KSHV specific probes on biopsies of Kaposi s's sarcoma, lymphoid and genitourinary tissues from HIV infected individuals in order to identify subjects who are latently or productively infected with KSHV; 2) use recombinant vaccinia and bacterial expression systems to produce KSHV gene products for immune assay; 3) develop assays to detect and quantify the CD4+ T cell response to KSHV proteins and perform these assays on T cells from individuals in various stages of HIV infection with and without Kaposi's sarcoma and/or body cavity lymphoma to determine the correlation between KSHV infection (lytic or latent), KSHV specific CD4+ T cell response and clinical manifestations and course; 4) develop assays to detect and quantify the CD8+ CTL response to KSHV and use these assays to determine the correlation between KSHV infection, KSHV specific CTL frequency and clinical manifestations and course; and 5) generate KSHV specific CD8+ CTL clones and utilize these clones in combination with synthetic peptides corresponding to known MHC class I binding motifs to identify KSHV-specific CTL epitopes; use dendritic cells pulsed with recombinant KSHV proteins and/or synthetic peptides to evaluate the ability of naive T cells to respond to these antigens. The results of these studies should lead not only to an improved understanding of the role of T cell mediated immunity to KSHV in the development KS and other AIDS associated tumors but, in addition, should lead to the identification of KSHV epitopes that can ultimately be used in a prophylactic or therapeutic vaccine.
| Herndier, B; Ganem, D (2001) The biology of Kaposi's sarcoma. Cancer Treat Res 104:89-126 |
| Gobbi, A; Stoddart, C A; Malnati, M S et al. (1999) Human herpesvirus 6 (HHV-6) causes severe thymocyte depletion in SCID-hu Thy/Liv mice. J Exp Med 189:1953-60 |
| Orenstein, J M; Alkan, S; Blauvelt, A et al. (1997) Visualization of human herpesvirus type 8 in Kaposi's sarcoma by light and transmission electron microscopy. AIDS 11:F35-45 |
