MECHANISMS OF PATHOGENESIS AND RECOVERY IN FRIEND RETROVIRUS-INDUCED LEUKEMIA

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Friend virus (FV) is a complex of 2 mouse retroviruses which induce rapid erythroleukemia in many strains of adult mice. Various genes in susceptible mice can modify the outcome of FV infection. Our laboratory has identified 5 such genes including 4 major histocompatibility complex (MHC) regions (D, IA, IE and T) and one non-MHC gene, Rfv-3. These genes all influence the host immune response to FV and FV leukemia cells and can even induce spontaneous recovery from leukemia or facilitate successful protective vaccination against challenge with live FV or FV leukemia cells. This year, using microsatellite mapping methods, the location of the Rfv- 3 gene was identified to be on mouse chromosome 15. Rfv-3 is known to influence the ability of mice to make a humoral antibody response to FV during the course of active infection. Mice with the Rfv-3r allele make anti-FV antibodies and clear FV viremia 2-3 weeks after infection. This is necessary, but not sufficient, for recovery from FV leukemia. The mechanism of the Rfv-3 gene function on the host immune response is not known, but the location of the gene indicates that it is near a T cell antigen gene (Ly6) and 3 cytokine receptor genes (IL2rb, IL3rb1, and IL3rb2). Future experiments will be aimed at identifying the mechanism of action of this gene. Other experiments have shown that mice lacking the Rfv-3r allele can still recover from FV leukemia if they are inoculated with high doses of anti-FV antibody. This antibody therapy was effective even if initiated after the peak of virus spread in vivo. However, recovery associated with antibody therapy also required T cell-mediated immune mechanisms because no recovery was observed in CD4- or CD8-depleted mice. These results indicate that recovery from Friend retroviral infection is dependent on the cooperative effects of several difference immune mechanisms including T helper cells, cytotoxic T and antibodies, and antibodies. The results imply that similar mechanisms might be effective in treatment of HIV infection with antibody therapy.