1. We are assessing the safety of AAV vectors and have produced a recombinant AAV vector encoding the human IL-2 receptor a and neomycin resistance genes. We are currently examining vector sequence stability during manufacture and the biologic consequences of inflammatory conditions upon AAV transgene expression and stability. 2. Cross-species infectivity is a primary concern for xenotransplantation. We are cloning and characterizing porcine endogenous retroviruses directly infectious for human cells. 3. Interleukin-12 has been shown to possess extreme toxicity depending upon the time course of administration. We have defined the promoter of the IL-12 p35 subunit in human monocytes and show that its recognition and function is regulated by interferon-g. 4. Chemokines are an newly recognized class of cytokines mediating inflammation, cell recruitment and viral infectivity. We are examining the role of chemokines in normal and disease states. 5. We developed an RT PCR model system and adapted it to evaluate cross-species transfer of porcine endogenous retrovirus. Gene therapies demonstrate toxicities mediated in large part through inflammation. The studies described above (1,3,4,5) examine key elements of this process. Cross-species infectivity is a primary public health concern for xenotransplantation. Studies 2 and 5 address porcine endogenous retrovirus in porcine xenotransplantation.
