Human immunodeficiency virus (HIV) has an extraordinary survival advantage, confounding existing therapies. With a short generation time, variable antigenicity, and a large number of infective virions, it is hardly surprising that despite the development of anti-viral pharmaceutical compounds, we have managed to only delay the onset of the fatal acquired immunodeficiency syndrome (AIDS). Novel antiviral therapy, specifically the insertion of genes which endow lymphohematopoietic cells with life-long protection against lentivirus infections offers a fresh approach to combating HIV infection. To date, the utility of this therapy has been hampered by the small number of hematopoietic stem cells available for transfection. We are poised to overcome these impediments by using a virtually limitless source of fetal hematopoietic cells (FHC) which are rich in immunologically-naive stem cells. By increasing the cell target numbers for transfection and transplantation we will be able to more rapidly determine the efficacy of stem cell gene therapy for treatment lentivirus infection. The animal model system we will employ is the feline immunodeficiency virus (FIV) in cats. FIV is a naturally-occurring retrovirus of domestic cats that provides valuable resources for understanding mechanisms of pathogenesis and for development of effective antiviral therapy and vaccines with direct relevance to HIV. The current proposal is to develop ribozyme based antiviral gene therapy against FIV infection in cats by targeting the regulatory gene rev and its cognate recognition sequences, rev response element (RRE), which are critical for virus replication. Antiviral sequences against rev and RRE will be delivered into cats using retroviral vectors by way of FHC. The long term goal of this research is to use this animal-model of HIV infection to determine whether decreasing retrovirus burden by myeloablation of a life-long source of blood cells, which are prophylactically protected against retrovirus infection, might provide a new therapy for individuals infected with HIV.
