This proposal addressess immunological and intracellular mechanisms of protection against feline immunodeficiency virus (FIV) infection provided by previous exposure to an apathogenic strain of FIV of puma origin (FIV-Pco). FIV-Pco is indigenous to pumas but can infect domestic cats without causing disease. Moreover, preliminary studies indicate that FIV-Pco may provide protection against virulent domestic cat FIV. This observation is relevant to HIV immunoprophylaxis since most successful vaccine trials in non-human primates have utilized avirulent but infective lentiviruses. The parameters critical to this observed immunity or interference have yet to be defined. The aims of this proposal, therefore, will be to: (1) verify that FIV-Pco will consistently infect domestic cats without causing clinical disease yet protect against virulent FIV infection; (2) evaluate protective intracellular mechanisms and humoral and cell-associated immunity which may account for FIV-Pco protection; and (3) establish the avirulence of FIV-Pco in neonates and immunologically suppressed adults. In vivo resistance to virulent FIV will be assessed by monitoring clinical disease, infectious virus, and immunological parameters in cats pre-infected with FIV-Pco then challenged either by injection or mucosal exposure to an acutely pathogenic strain of FIV. Potential mechanisms of interference between FIV-Pco and FIV will be examined in vitro. Finally, neonatal cats and adult cats immunosuppressed by corticosteroid treatment will be challenged with FIV-Pco to determine if the virus remains avirulent in the face of host immune compromise. These studies will examine the basis of protection provided by avirulent lentiviruses as potential vaccines in a facile animal model system.