The ultimate sequelae of HIV infection in humans are loss of CD4 T cells, immune system compromise, susceptibility to opportunistic infections and unusual neoplasms, and eventual death. Although the direct cytopathic effects of HIV on CD4 cells are undoubtedly important in AIDS pathogenesis, these effects do not appear to fully account for the severe immunodeficiencies associated with the disease. Products of bacteria, mycoplasmas and viruses with superantigenic properties engage large sets of T cell clones almost solely on the basis of VBeta expression. T lymphocyte engagement by superantigens leads to anergy of expansion and eventual apoptotic death of the engaged cells. Superantigens of HIV or other secondary microbial pathogens may contribute to the CD4 loss that typifies AIDS either directly or indirectly by promoting infectivity and replication of the virus. Recent data suggest that AIDS is associated with deletion of specific VBeta clone, HIV exhibits preferential infectivity of certain VBeta clone types and T cells from AIDS patients are prone to apoptosis, all possible manifestations of superantigenicity. The studies proposed herein will determine whether VBeta clonal changes are characteristic of AIDS and are involved in the pathogenesis of this disease by examining VBeta repertoires in HIV-infected patients from all disease groups, including monozygotic twins discordant and concordant for this disease. Moreover, possible superantigenic activities of HIV will be assessed in vitro by examining VBeta stimulation in HIV-infected syngeneic cultures, degree of infectivity for malignant, VBeta transfected or bacterial superantigen-stimulated T cells expressing specific VBetas, and effects of HIV on the developing human immune system in thymic organ cultures. The VBeta genes represented in HIV recombinant protein-specific T cell clones will also be ascertained. In vivo induced clonal loss of HIV and related proteins will also be evaluated in the SCID mouse-human fetal thymus/liver model. The combined studies will provide important clues to the pathogenesis of AIDS-associated immunodeficiency, and will have significant implications for the prognosis, follow-up and treatment as well as etiologic basis of this epidemic disease.
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