Human Herpes Virus Associated with Kaposi's Sarcoma (KS)

Ornella Flore, Ph.D.
The research in my laboratory focuses on a recently discovered human herpesvirus, Kaposi's sarcoma-associated herpesvirus (KSHV) also called human herpesvirus 8 (HHV-8) linked to Kaposi's sarcoma. KSHV/HHV8 is a gammaherpesvirus and its DNA has been found to be present in all epidemiologic forms of Kaposi's Sarcoma (KS), including classical, endemic-African and AIDS types of KS as well as an uncommon but recognized complication in patient with organ transplants. This tumor has a complex pathology exhibiting spindle cells derived from heterogeneous population of cells, abnormal angiogenesis and production of cytokines. The tumor genesis likely depends on viral replication within an immunologically impaired host. Epidemiological evidence has long implicated a transmissible agent in the etiology of Kaposi's sarcoma. Its high prevalence in homosexual men with AIDS and relative scarcity in drug users and hemophiliac patients is one such suggestive observation. In addition KSHV/HHV8 is also associated with lymphoproliferative disorders including PEL (Primary Effusion Lymphoma) and multicentric Castleman's disease (MCD). These lymphomas have allowed the establishment of KSHV-latently infected cell lines that, with appropriate stimuli, can produce infectious viral particles in culture.

Our studies include two major areas. The first is to further elucidate the processes by which HHV-8 induces the transformation and long term proliferation of primary human endothelial cells and keratinocytes in culture. Our experiments are aimed at understanding the molecular biology and the angiogenic pathways involved in KSHV/HHV-8 mediated tumor pathogenesis. KSHV/HHV-8 appears to use mechanisms, which are different from those of other transforming viruses, including paracrine effect, signal transduction, which regulates cell proliferation, differentiation and apoptosis, the self-induced death of infected cells. We approach these aims by examining viral gene expression and viral-host protein interactions.

The second is to further study some drugs which inhibit the viral latent genes expression or the switch of KSHV from latency to lytic cycle and to relate these findings to the pathogenesis and eventual treatment and/or prevention of Kaposi's sarcoma and primary effusion lymphomas. We approach these aims by examining viral gene transcription and expression in treated and untreated cells and potential cellular apoptosis.