A highly pathogenic variant of FIV, subtype C, has been identified by serial passage of a clinical isolate. FIV-C infection is characterized by high acute phase viral RNA burdens, CD4 T cell depletion, wasting, opportunistic infections, and death of about50 percent of cats by 16-18 weeks post infection. The purpose of the present proposal is to investigate and define the molecular basis for the pathogenic potential of this unique isolate by obtaining an infectious molecular clone, identifying changes in its protein sequence relative to other less pathogenic FIVs, and using chimeric viruses prepared between FIV-C and the well-characterized less pathogenic FIV-PPR to map the pathogenic determinants of FIV-C. Particular emphasis will be placed on the preparation and testing of env gene recombinants. Viral cell tropism, both in vivo and ex vivo, will be assessed to determine the relative host cell range potential of parental and chimeric FIVs to reveal relatedness to disease potential. For example, FIV-C appears to lack the CNS tropism of FIV-PPR but produces more severe T cell depletion. Defining the molecular determinants of pathogenesis in this system will advance the FIV model and help to better understand the mechanisms of lentivirus infection and intervention.