Serious anemia or neutropenia occur in nearly 50% of patients infected with human immunodeficiency virus (HIV) who are treated with azido- deoxythymidine (AZT). The pathogenesis of these changes is not well characterized but is likely to involve effects of the virus on hematopoietic progenitors or bone marrow stromal cells that regulate hematopoiesis. The overall objective of this study is to use the naturally occurring and experimentally reproducible model of feline leukemia virus (FeLV)-induced myelosuppression to investigate mechanisms of hematopoietic suppression and to develop methods for effective treatment. Cats with persistent FeLV infection are markedly immunosuppressed and develop a variety of infectious, neoplastic, or myelosuppressive diseases which resemble AIDS. Experimental infection of cats with the Kawakami-Theilen isolate of FeLV results in variable neutropenia and erythroid aplasia.
The specific aims are to investigate the effects of feline leukemia virus on cells of the bone marrow stroma, determine the mechanism and role of stromal cell injury in retrovirus-induced hematopoietic defects, and evaluate potential methods for counteracting the inhibitory effects of retroviruses and AZT on hematopoietic cells. Sequential biopsies of bone marrow will be evaluated for morphologic and cytochemical evidence of infection or injury of critical cells of the bone marrow stroma. Long-term bone marrow cultures, clonal assays for hematopoietic progenitors, and cultures of fibroblastic cells of the bone marrow stroma will be used to investigate mechanisms of retrovirus-mediated inhibition of bone marrow stromal cells. Transplantation of autologous bone marrow cryopreserved prior to infection with FeLV and clonally expanded populations of uninfected autologous bone marrow stromal cells will be used to reconstitute the marrow of infected animals. The pharmacologic induction of endogenous production of hematopoietic growth factors will be evaluated as a method of counteracting the hematopoietic suppression in retrovirus- infected animals being treated with AZT.
