Dengue virus infections are a significant cause of morbidity and mortality in many areas of the world and are an emerging threat to the USA. Epidemiological studies have shown that the severe complications of infection, dengue hemorrhagic fever (DHF), are much more commonly observed during secondary infections with a different serotype of dengue virus from that which caused the primary infection. 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. We hypothesize that dengue virus-specific T cells which are activated in vivo in patients with DHF play an important role in the pathogenesis of DHF and also contribute to the recovery from infection. We will analyze these in vivo activated T cells in patients with DHF or dengue fever (DF) in bulk culture and at the clonal level. We will quantitate the number of 1) dengue-specific T cells among activated T cells, and 2) lymphokine-producing T cells. We will analyze dengue virus-specific T cells at the clonal level for 1) dengue serotype specificities, 2) protein recognition, 3) recognizing epitopes and 4) HLA restriction. We will also determine whether in vivo activated T cells in DHF or DF become memory T cells after recovery, using T cell receptor sequences as a marker. There are many regions of the world where multiple flaviviruses including dengue viruses are prevalent. We will analyze flavivirus -crossreactive T cells and antibodies in order to examine a role for flavivirus-crossreactive immune responses in the pathogenesis of DHF. We will determine whether dengue virus-responsive T cells and dengue virus-enhancing antibodies are induced by infection with other flaviviruses. We will also define flavivirus-crossreactive T cell epitopes. These results will provide basic information about the roles of dengue virus-specific or flavivirus-crossreactive T lymphocyte responses in the pathogenesis of DHF or in the recovery from dengue virus infections.
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