The goal of this proposal is to evaluate the role of programmed cell death in the control of viral infections, in the down-regulation or silencing of the immune response and conversion into memory, and in the development of the transient immune deficiency that is characteristic of most acute systemic viral infections. The lymphocytic choriomeningitis virus (LCMV) infection of mice will be used as a model system to generate activated natural killer (NK) cells and cytotoxic T lymphocytes (CTL). The first specific aim evaluates the role of cell quiescence on the ability of NK cells and CTL to induce apoptosis in target cells, as we have shown that quiescent cells don't fragment their DNA during CTL attack. The effects of infections with viruses such as herpes simplex, vaccinia, and murine cytomegalo on the susceptibility of the targets to apoptosis will be studied. Analyses will be made concerning whether viral DNA fragments in cells attacked by CTL and whether quiescent cells in vivo fragment their DNA. The second specific aim deals with an analysis of programmed cell death in vivo during LCMV infection and in vitro upon T cell receptor stimulation of LCMV-induced T cells, which we have shown rapidly undergo apoptosis during a window of time in which there is immune deficiency. A variety of genes shown to be involved in apoptotic pathways in other systems will be examined, using in situ hybridization and transgenic mice techniques. The third specific aim focuses on the phenotype of virus- induced memory T cells and the hypothesis that memory T cell responses to unrelated antigens are compromised by acute viral infections due to an out of sequence stimulation of the memory cells with growth factors before exposure to antigen. The significance of this work is that it will contribute to an understanding of what may be a universal mechanism of virus-induced immune deficiency.
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