Infection with the Kaposi's sarcoma-associated herpesvirus (KSHV) is common around the world and affects more than half of all HIV-infected individuals. This newly described virus has been implicated in virtually all cases of primary effusion lymphoma (PEL), an unusual but universally deadly complication of AIDS and organ transplantation. PEL is unique among B cell lymphomas in that these cells accumulate suspended in the pleural, pericardial or peritoneal cavities of the body. The reason for this tropism is completely unknown. In preliminary experiments we have shown that multiple PEL lines express a novel and uniform chemokine receptor phenotype not previously reported for other lymphomas or normal B lymphocytes. PEL cells demonstrate directed movement in response to chemokines for which they bear the appropriate receptors. Acellular effusions from PEL patients cause specific attraction of PEL cells in vitro, a finding that is amplified and confirmed in a new mouse model we developed for lymphocyte migration to the peritoneal cavity. Furthermore, this phenotype can be imparted to a non-PEL lymphoma cell line by transfecting genes from the latency program of KSHV. We hypothesize that chemokine-driven directed migration attracts and sequesters KSHV-infected PEL cells in the body cavities, and that expression of KSHV latency genes may be responsible for establishing this unique tropism. Thus, PEL homing may represent a novel target for interrupting the virus-associated development and progression of this high-grade lymphoma. The goal of this proposal is to further elucidate what role KSHV plays in the body cavity tropism of PEL cells, to determine whether the process is chemokine-related, and to identify the molecular components of the homing process. These studies constitute part of a training program that will build on the investigator's previous immunology experience by expanding his facility with virologic principles and molecular biology techniques through coursework, intense interaction with a dedicated mentor and monitoring committee, and scientific partnership with collaborators, and an outstanding research environment. This award will substantially advance the candidate's goal of developing an independent basic science research program in a university setting while contributing new training in infectious disease and oncology to the development of new perspectives on the inflammatory diseases.
