Feline immunodeficiency virus (FIV) infection in cats is the only non-primate, small animal model for HIV-AIDS. Replication of FIV has been shown to be optimally suppressed by soluble factors produced by inducer cell-stimulated feline CD8+ cells from FIV-infected cats. The nature of this dose-dependent suppression of FIV was examined. Antiviral factors, produced in serum-free medium, were shown to be either heat stable or heat labile. Suppressing activity was identified in a heparin-bound fraction and the non-bound fraction and in fractions separated by reverse-phase HPLC. The FIV suppression could not be correlated with IFN type I or II. Neither alpha nor beta chemokines were likely candidates because molecular size exclusion centrifugation indicated that the major factors were larger than 50 kD. Identified qualitative differences in the properties of the soluble suppressive activity generated from feline lymphocytes indicated that multiple factors are responsible for the non-cytolytic CD8+ T cell suppression of FIV replication.