We propose a detailed study of the mechanism of induction of MAIDS. B6 mice inoculated with the BM-5 retrovirus mixture develop a severe disease which includes immunodeficiency, lympho-proliferation, frequent development of lymphoma and death. One facet of disease is an early alteration in the CD4 subset of T cells which suggests that they have undergone a kind of polyclonal activation which has caused their proliferation, but resulted as well in their immunodeficiency. Because the CD4 T cell subset is required for the disease to be initiated and to progress, it is likely that these changes in CD4 T cells play a key role in the disease process. We plan to identify the subset(s) of CD4 T cells that undergo the phenotypic conversion and identify that which is required for disease. We will examine the contribution of naive and memory CD4 T cell subsets and evaluate whether the response has the hallmarks of antigen or superantigen induced anergy. Cloned, expressed defective virus gp-60 polyproteins will be directly tested for superantigen activity. We will evaluate whether the virus somehow perturbs selection in the thymus or whether the mechanism of action is restricted to the periphery. We will also investigate what cell types harbor defective virus, and synthesize viral products. We will evaluate the frequency of T cells which respond and whether they proliferate a little or a lot. We will also determine the lymphokines produced during disease, identity the cell type(s) that is synthesizing them and investigate whether blocking the action of selected lymphokines interferes with disease. These studies will be pursued both in vivo and also in an in vitro model that we are attempting to develop. In the in vitro model we hope to identity the actual cell interactions involved in CD4 conversion in MAIDS. We expect that these results will reveal important principles about the mechanism of host-virus interaction in this particular retrovirus mediated disease. Since there are many parallels between MAIDS and AIDS, we expect that the results will also provide more general insight into the mechanism which may be generally involved in the induction of immunodeficiency disease.
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