MOUSE RETROVIRUS CO-OPTING OF IMMUNE CELL INTERACTIONS

Dartmouth College, Hanover NH

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Abstract

The LP-BM5 isolate is a complex of murine leukemia viruses (MuLV). It includes replication competent helper viruses for packaging a defective viral genome that encodes only a unique gag polyprotein and is the proximal etiologic agent causing disease. LP-BM5 retrovirus infection of susceptible mouse strains, such as C57BL/6 (B6), leads to a complex disease syndrome with several profound features. Among these are: 1) early polyclonal B cell activation and proliferation, 2) hypergammaglobulinemia, 3) generalized proliferation of lymphocytes and lymphadenopathy, 4) severe immunodeficiency of both T- and B-cell responses, 5) increased susceptibility to progressive infections by environmental pathogens that cause only inapparent infections in normal mice, and 6) an increased incidence of tumors, particularly terminal B-cell lymphomas. Because this disease has some similarities to AIDS, it has been termed "murine AIDS/MAIDS." However, the real value of studying MAIDS is as a very dramatic and intriguing disease itself that illustrates the strategy of retroviral co-opting of immune interactions for pathogenesis. The viral pathogenesis of LP-BM5 induced MAIDS is incompletely understood. Although it is clear that both B cells and CD4+ T cells are required for the initiation of MAIDS, early studies did not define the mechanism of disease induction. Most studies have focused on kinetically "downstream" events, for example, the effects of MAIDS on CD4+ T cells, such as their anergic state. In contrast, our studies have concentrated on defining the early cellular and molecular interactions required for establishing disease. Our novel findings have included demonstrating a requirement for B cell-CD40/CD4+ T cell- CD40L (CD154) interactions for both the initiation and progression of MAIDS. The extensions of these studies proposed here will further define the cellular and molecular bases for the CD4+ T cell/B cell interaction, and the CD40-mediated signaling consequences following ligation by CD154, that are necessary for LP-BM5 induced MAIDS. The specific aims are: 1) to determine which cellular compartments must be infected by LP-BM5 and express def-gag for MAIDS pathogenesis, 2) to define the phenotypic and/or functional characteristics of CD154+ CD4+ T cells critical for their interaction with B cells and the induction of LP-BM5-mediated MAIDS, and 3) to further characterize the requirements for B cells, specifically CD40 stimulation of B cells, for LP-BM5 induction of MAIDS.