The role of Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8) in lymphoproliferative diseases.

The Kaposi's sarcoma-associated herpesvirus (KSHV), also called human herpesvirus 8 (HHV-8), is found invariably in Kaposi's sarcoma, and compelling evidence suggests that it is an etiologic agent for this disease. KSHV has also been found to be present in a limited subset of lymphoproliferative disorders. Among these are the primary effusion lymphomas, formerly designated body cavity-based lymphomas. This is a rare type of malignant lymphoma which possesses an unusual set of clinical and biologic features, suggesting that it represents a distinct disease entity. This virus is also present in a large proportion of cases of multicentric Castleman's disease, particularly those associated with HIV infection. In addition, KSHV has been implicated in the pathogenesis of multiple myeloma, but many laboratories including our own have been unable to confirm this association. KSHV carries at least 11 open reading frames (ORFs) that encode homologs to cellular proteins involved in signal transduction, cell cycle regulation, inhibition of apoptosis and/or immune modulation. Therefore, it has the genetic machinery of an oncogenic virus. However, only a small proportion of infected people ever develop Kaposi's sarcoma or virus-induced lymphoma, and do so only after a long latency period. This observation reflects the multistep nature of oncogenesis, with viral infection representing only one of these steps. Cofactors such as HIV infection and iatrogenic immunosuppression dramatically increase the risk for developing a KSHV-related malignancy in infected individuals. Understanding the oncogenic and immunologic mechanisms involved in the pathobiology of virus-associated lymphomas is important for the development of targeted therapeutic and preventive approaches.