The Viral Oncology Program currently has an emphasis on AIDS associated malignancies, innate immunity, and tumor cell biology. Among the active areas of research are the following projects.
Marvin Reitz, Ph.D., Shibani Pati, M.D.,Ph.D., and William Reid, D.V.M., are currently studying the contributions of the human herpes virus 8-encoded G protein-couple receptor (vGPCR) to Kaposi's sarcoma (KS) pathogenesis, using a vGPCR transgenic mouse model and a vGPCR-dependent nude mouse xenotransplant model of KS. They are also characterizing pro-angiogenic and pro-inflammatory signaling pathways activated constitutively by the vGPCR in vitro. They are studying the mechanisms by which the HIV-1 Tat protein potently increases both in vitro signaling and tumorigenesis by vGPCR and the role of vGPCR-mediated angiogenesis in tumor formation.
David Pauza, Ph.D., is interested in the role of Vγ2/Vδ2 T cells in cancer surveillance and in learning how to exploit this cell population for cancer therapy. The immediate challenges are to define the mechanisms for tumor cell killing and to perform preclinical studies of adoptive transfer in nonhuman primates. The ultimate goals are to understand what role γδ T cells play in innate immunity to tumors and to accumulate foundational preclinical data to enable future clinical studies on transfer of ex vivo-expanded γδT cells into post-therapy patients to destroy remaining tumor cells, initially targeting leukemia, lymphoma, and myeloma.
Fabio Romerio, Ph.D., in collaboration with Dr. Amy Fulton, is currently investigating whether regulatory T cells represent a mechanism of immune suppression that allows HIV to inhibit protective immune responses. Regulatory T cells prevent infection-induced inflammatory disease and immunopathology by suppressing Th1 and Th2 immune responses. Several chronic pathogens and types of cancer - such as breast cancer - induce the generation of regulatory T cells, which could limit protective immune responses and allow unchallenged tumor growth. Dr. Romerio has taken advantage of an in vitro culture system whereby exposure of PBMC to HIV induces the generation of a cell population that suppresses the proliferation of autologous PBMC. This in vitro system may be amenable to investigate interactions between the immune system and tumor cells and to study how malignant cells are able to generate an immune suppressed microenvironment.
Robert C. Gallo, M.D., and Joseph L. Bryant, D.V.M., are studying anti-tumor and pro-hematopoietic activities of early pregnancy-related factors present in first trimester pregnancy urine, called maternin. Maternin appears to induce apoptosis in tumor xenotransplants in nude mice, including Kaposi's sarcoma xenotransplants, but the effects are more consistent and greater in vivo than in vitro, suggesting an anti-angiogenic mechanism. We are continuing purification and characterization of other active native material that has greater direct in vitro pro-apoptotic effects. Maternin also appears to have pro-hematopoietic effects, as judged by stimulation of colony formation in vitro by hematopoietic blood cells.
Mikulas Popovic, M.D., Ph.D., Robert C. Gallo, M.D., Joseph L. Bryant, D.V.M., and Dean Mann, M.D., have been studying the possible role of HIV in the B-cell lymphomas that are seen with an increased incidence in AIDS. Because HIV-1 proteins persist for a long time in germinal centers (GCs) of lymph nodes in infected individuals even in absence of HIV-1 replication, they hypothesize that HIV-1 proteins persisting in GCs interact with lymphoid cells and contribute to development of non-Hodgkin lymphomas. 40% of old HIV transgenic mice develop B-cell lymphomas similar to that observed in HIV infected humans. The role of HIV proteins in induction of these murine B-cell lymphomas is under study.