Individuals infected with the human immunodeficiency virus (HIV) develop a degenerative disease of the immune and central nervous systems that is accompanied by a broad spectrum of opportunistic infections. During early stages of the acquired immune deficiency syndrome (AIDS) epidemic, an association of AIDS and certain kinds of neoplastic transformation became apparent. With the advent of new and better agents to treat opportunistic infections resulting in longer life spans for AIDS patients, a significant increase in the incidence and kinds of malignancies associated with AIDS has been observed. Our long-term objective is to study the role that the regulatory genes of HIV play in AIDS-associated neoplasia. Evidence has been presented indicating a possible association between the HIV-tat protein and the development of Kaposi's sarcoma. We propose to establish a small animal model to study the role that tat play in the development of AIDS-associated Kaposi's sarcoma. We will use retroviral-mediated gene transfer to introduce a functional tat gene into murine bone marrow in vitro. This genetically-modified bone marrow will then be used to repopulate recipient animals after bone marrow transplantation. We will study the in vivo expression and functionality of this gene in the hematopoietic system of these animals. We will study the role that expression of this gene may have in the development of Kaposi's sarcoma or other significant pathology in vivo. We will study the contribution of hematopoietic cells to the KS lesion, and we will study the effect of male- and female-specific hormones in the development of Kaposi's sarcoma. Finally, because the transferred genes are only expressed in the hematopoietic system, more meaningful correlations can be drawn between the effects noted and what is observed in infected individuals. The animal model that we propose might serve as a test system to treat AIDS-associated Kaposi's sarcoma.
