T cell regulation during viral infections is a complex process consisting of antigen-specific stimulation and apoptotic elimination. We have shown in the murine lymphocytic choriomeningitis virus (LCMV) model, that highly activated T cells become sensitized to undergo apoptosis on antigen receptor-triggering (activation-induced cell death [AICD]) and that this correlates with transient immune deficiency, an event seen in many human viral infections such as HIV, EBV, and CMV. This decline in T cell number following resolution of infection (immune silencing) correlates with apoptosis in T and B cell populations in vivo. The great majority of virus-induced activated T cells are virus- specific (though often crossreactive with other antigens), and this T cell response greatly perturbs the memory T cell pool, leaving the host with substantially less T cell memory to prior pathogens after immune silencing has occurred. Others have shown that very high doses of LCMV lead to the clonal exhaustion of CTL, and we have shown that an anti- apoptotic Bcl-2 transgene markedly alters pathogenesis in this model. Here we will examine how apoptotic processes contribute to immune deficiency and to naive and memory T cell regulation in virus infections. We propose to examine apoptosis and cell attrition in virus-specific and nonspecific lymphocyte populations during viral infections, to evaluate how apoptotic mechanisms contribute to virus- induced immune deficiency, to analyze memory cell attrition occurring during sequential viral infections, to evaluate the role of interferons as possible proapoptotic cytokines, and to examine the functions of CD4 T cells and the anti-apoptotic Bcl-2 gene under conditions of clonal exhaustion. By manipulating this highly defined LCMV model in vivo, fundamental concepts concerning immunoregulation and immune deficiencies applicable to human viral infections should be obtained.
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