Dengue virus infections are a serious cause of morbidity and mortality in many areas of the world. The pathogenesis of severe complications of dengue virus infection, dengue hemorrhagic fever (DHF) is important to elucidate for prevention and treatment of DHF. Epidemiological studies have shown that DHF is much more commonly observed during secondary infections with a different serotype of dengue virus from that which caused the primary infection, and it is assumed that DHF is caused by immunopathological mechanisms. We hypothesize that enhanced infection of monocytes by dengue virus-antibody complexes results in marked activation of dengue virus-specific CD4+ and CD8+ T cells and the production of high levels of cytokines which lead to DHF. The goal of this project is to define immunopathological mechanisms which induce DHF, using molecular immunological techniques. No animal models are available to study DHF; therefore, research using human subjects is required. We will elucidate immunopathological mechanisms by analyzing peripheral blood mononuclear cells (PBMC) and plasma of patients with DHF or with uncomplicated dengue fever (D) during the acute phase and after recovery. We will; 1) determine the levels of lymphokine mRNA in CD4+ and CD8+ T cells activated in vivo, 2) determine whether dengue virus-specific CD4=T cells in patients with DHF are Th1 or Th2 by establishing CD4+T cell clones, 3) determine whether dengue virus-specific CD8=T cell clones also produce a characteristic set of lymphokines, and 4) analyze T cell receptor Valpha and Vbeta gene usage and determine whether T cell activation is oligoclonal in vivo. Monocytes are the most permissive human cells for dengue virus replication. We will determine the levels of cytokine mRNA in monocytes from patients with DHF or D. Furthermore, we will determine the levels of infectious dengue virus-antibody complexes in the plasma of patients with DHF. The comparative ability of virus isolates from D and DHF patients to replicate in human monocytes will be tested in tested in this project. If significant differences in growth are detected, we will use this as a biologic marker for selecting typical strains for genome sequencing in project 3. We will define the immunological responses in vivo which result in DHF, based on these analyses of samples from patients with DHF or D. These analyses will provide basic immunological data concerning antibody and T cell responses to dengue virus that are needed for the development of safe and effective dengue vaccines.
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