MOLECULAR ANALYSIS OF POLIOVIRUS NEURTRALIZING EPITOPES

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The success of the poliovirus vaccines have strongly influenced current concepts about how vaccines work. These concepts in turn have formed the present underlying theoretical framework for many of the strategies in vaccine development and vaccine efficacy assessment. However, these concepts were developed prior to our knowledge of cell-mediated immune (CMI) responses and little direct information exists that explains the mechanisms by which an individual's immune responses protects against disease development. Clearly, elucidation of poliovirus-specific humoral and CMI responses is critical to an understanding of how these responses protect the host against disease. To achieve these goals, the specific aims are the following: l. The "anatomy" of the immune response will be characterized by determining whether T helper and cytotoxic epitopes colocalize to previously determined poliovirus neutralizing antigenic sites and by characterizing the nature of the virus-specific T lymphocyte population. These studies will examine whether T epitope selection is influenced by the sequence environment and whether identification of neutralizing antigenic sites will provide general criteria for identifying T epitope rich regions. In addition, the subtypes of T lymphocyte populations present in the induced response will be determined. Similar studies will be performed in poliovirus-permissive transgenic mice (TgPVR) after viral infection. The results will be compared with that observed in normal C57BL/6 mice to determine whether immune responses are identical in susceptible vs. nonsusceptible hosts. 2. The in vivo roles of the humoral and CMI responses in disease production and/or host protection will be defined using bulk poliovirus specific T cell populations, T cell clones of defined specificities, and monoclonal antibodies of defined specificities. Adoptive transfer and passive immunization studies will be performed in experimentally infected poliovirus permissive transgenic mice. These studies will examine the relative roles of T and B lymphocytes in virus clearance, virus spread and pathology and ultimately host protection. Characterization of the immune response induced upon viral infection or vaccination is necessary to understanding the molecular basis of disease. Although the humoral response induced by poliovirus has been extensively studied by this and other laboratories, the cell-mediated immune response (CMI) has remained relatively uncharacterized. The aim of the proposed research is to develop a more detailed molecular description of the poliovirus-specific CMI response and to study the in vivo role of the CMI and humoral responses in disease protection.