Studies have been undertaken to evaluate the immunopathogenesis of MAIDS, a murine immunodeficiency disease produced by infection with a mixture of LP-BM5 retroviruses. Specifically we are assessing 1) the response to infection by susceptible and resistant lymphoid populations, 2) the contribution of allospecific responses to generation of disease, 3) the contribution to infection of non-lymphoid host target tissues, and 4) the role of macrophages in induction and maintenance of infection. 1) Susceptible B6 mice develop MAIDS within 8 weeks of infection whereas resistant 129 strain mice do not develop infection in over 8 months. To test whether resistant cells could modify the course of infection in susceptible animals, we infected B6<->129 allophenic mice, whose lymphoid compartments were chimeric in that they contained cells of B6 (susceptible) origin and cells of 129 (resistant) origin, with LP-BM5. Surprisingly, these animals developed accelerated lymphadenopathy and splenomegaly relative to control B6 mice, indicating that the presence of resistant cells was not sufficient to suppress infection. However, this occurred in animals in which only a maximum of 35% of the lymphoid compartment was composed of resistant cells. Experiments are in progress to assess whether infection can be modulated when the percentage of resistant cells is higher. 2) Retroviruses initiate disease by inoculation either as a cell free extract or in a cell associated form. In the case of HIV infection, presentation of cell associated virus transpires across allogeneic histocompatibility barriers. To understand the role of such effects, mice were inoculated with cell associated LP-BM5 retroviruses across MHC class I or MHC class II histocompatibility barriers and assessed for infection. Preliminary results reveal that relative to control syngeneically infected mice, accelerated disease was observed across MHC class II barriers and attenuated disease across MHC class I barriers. That this did not merely reflect differential susceptibilities of different strains to viral infection was shown by an equivalent rate of disease development in the three strains on inoculation of cell free virus. Further studies are being done to confirm these observations and to explore the mechanisms by which such effects are mediated. 3) It has been demonstrated that the course of MAIDS infection is dramatically attenuated by chemotherapy that obliterates the lymphoid and bone marrow compartments. Nonetheless, disease recrudesces following repletion of lymphoid cells indicating that other tissues may harbor LP- BM-85 virus and prove a source of reinfection. Previous studies indicate that skin cell populations may harbor LP-BM5 virus because disease may be transmitted via skin grafts from infected animals. We have found evidence by PCR analysis of provirus in skin samples of infected but no non- infected mice. Studies are underway to specifically identify which skin cells may harbor infective virus. 4) The role of the macrophage in generation of MAIDS from LP-BM5 infection is not clear. To assess contributions of the macrophage to disease generation, we are specifically depleting macrophages by injection of toxic liposomes into mice inoculated with LP-BM5.