The present project is a competitive continuation of grant Al 054455-01, and seeks to develop the IMMSIM computer model of host responses to its full potential as a supporting and predictive tool for infection research. This effort is carried out through a close multidisciplinary cooperation of modelers with immunologists working with viruses of the pox and arenavirus family, which both belong to the A category;therefore, the simulation may become of interest in the framework of the current NIAID Biodefense Research protocols. Two issues are central for the understanding of anti-virus responses: the changeable clonal hierarchy of T cell memory introduced by viral crossreactivity and the possible changes in efficiency of the defense. In both areas breakthroughs have been made in the last few years, which will eventually have important consequences in the planning of protection strategies. By incorporating these new T cell features, the model has enhanced its ability to simulate both acute and memory immune responses to infection. Hence the results of each series of runs can serve as verification of an hypothesis generated in vivo, or as the source of a new predictive hypothesis that will have to be challenged by in vivo experiments. The study will focus on: a) the nature of clonal dominance and clonal attrition, asking whether the signal for induced apoptosis is originated by competition for local resources or by global population constraints;b) the reasons for the apparent asymmetry of the effects of crossreactions, when two viral infections are enacted in reversed order;c) the shrinking of the clonal memory repertoire caused by heterologous challenge and/or attrition, and the evaluation of the biological consequences;and d) the possible advantage of using heterologous challenges (T- but not B-crossreacting) that could avoid neutralization by circulating antibodies and reach the immunocompetent cells with a full dose of antigenic stimulus, thus yielding a more predictable protection. Thus we propose the following specific aims: 1) to increase IMMSIM's modelling flexibility by incorporating the capability to modulate the level of T activation in relation to a number of factors of the stimulus;create a sufficiently large and degenerate repertoire of clonotypes in order to model T cell specificity and crossreactivity, in particular to simulate private specificities'responses to """"""""unrelated"""""""" viruses in vivo. 2) To run in machina immune responses to viral infections;to study the cases of npnsymmetric crossreaction with the relative affinity of clones to the infecting virus. 3) To quantify by in vivo and in vitro experiments the two factors concurring in the phenomenon of attrition. 4) To compare, in parallel in vivo-in machina procedures, the relative efficiency of homologous or heterologous T-cell-crossreactive (but B-cell- foreign) challenges to organisms pre-sensitized to a given virus. The relevance of this study to public health and to medicine in general stems from the introduction, to the well-established practice of vaccination, of new findings regarding cross-reactivity between different viruses and between the immune responses to different viruses. In particular, this study focuses on the pox and arena viruses, which have been designated as """"""""A-category"""""""" public health concerns.
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