Retroviruses cause severe immunodeficiency syndromes in various species including the mouse (mouse AIDS, MAIDS). We are studying MAIDS to develop a basic understanding of how retroviruses induces immune dysfunction. MAIDS is caused by a replication defective virus (BM5def) that encodes a variant 60kD gag polyprotein as its only product; replication competent helper viruses with normal gag higher levels in B cells and macrophages than T cells and expression in B cells is associated with abnormal signaling after immunoglobulin crosslinking. However, expression in lymphocytes is not sufficient to induce disease as mice deficient in expression of major histocompatibility complex class II molecules BM5def gag at high levels but do not develop MAIDS. Infection with BM5def results in enhanced expression of the cytokines Il- 4, Il-10, and IFN-gamma. MAIDS develops normally in mice with gene knockouts for Il-4, Il-10 or both cytokines, indicating that expression of these two cytokines is not required for disease. In contrast, disease develops more slowly in mice with an IFN-gamma knockout. Studies designed to investigate therapeutic strategies showed that immunization of mice with vaccinia carrying BM5def gag was infective. However, administration of IL-12 to infected mice prevented or greatly reduced the extent of virus-induced immune abnormalities. These results indicate that MAIDS results from a complex interplay of BM5def with cells of the immune system. Current studies are focused on determining if BM5def gag binds to particular cellular proteins and what interactions might affect cell signaling pathways that are altered during the course of disease.
