Proinflammatory cytokines secreted by memory CD8؉ and CD4 ؉ T cells are thought to play a direct role in the pathogenesis of dengue virus infection by increasing vascular permeability and thereby inducing the pathophysiologic events associated with dengue hemorrhagic fever and dengue shock syndrome. Severe disease is frequently observed in the setting of secondary infection with heterologous dengue virus serotypes, suggesting a role for cross-reactive memory T cells in the immunopathogenesis of severe disease. We used a large panel of well-characterized dengue virus-specific CD8 ؉ T-cell clones isolated from Pacific Islanders previously infected with dengue virus 1 to examine effector memory function, focusing on a novel dominant HLA-B*5502-restricted NS5 329-337 epitope, and assessed T-cell responses to stimulation with variant peptides representing heterologous serotypes. Variant peptides were differentially recognized by dengue virus 1-specific effector CD8

We investigated the duration of humoral responses to dengue virus infection in individuals who recalled experiencing dengue fever-like illnesses at the time of the Second World War, when dengue fever epidemics occurred throughout the Pacific and Southeast Asia. In July 1943 dengue fever reappeared in Hawaii following an interval of 31 years. Over the next 12 months a total of 1498 locally transmitted cases were reported, and at least 46 imported cases were identified, most of which were among members of the military returning from the Pacific Theatre of the war. Serum samples collected in 2005, more than 60 years after onset of symptoms, were tested for the presence of dengue-specific antibodies using a rapid ELISA test, and by plaque reduction neutralization test. Four of seven samples were positive for dengue-specific IgG and demonstrated neutralization titers ≥160 to dengue 1. We describe the existence of dengue-specific antibodies in the serum of people infected more than 60 years earlier. BRIEF REPORTDengue Viruses Are mosquito-borne single-stranded RNA viruses that belong to the family Flaviviridae. Infection with any of the four dengue serotypes (DENV-1, DENV-2, DENV-3, and DENV-4) can cause a spectrum of illnesses ranging from asymptomatic infection to severe hemorrhagic disease and shock syndrome, which can be fatal. Immunity to one dengue serotype following a first, or primary, infection does not protect against subsequent infection with any of the other three serotypes, and indeed, epidemiological observations suggest that severe disease occurs more frequently in the setting of secondary infection with heterologous virus (reviewed in 6 , 7). The pathogenesis of the severe forms of disease is not fully understood, but one hypothesis is based on the idea of antibody-dependent enhancement, in which preexisting non-neutralizing antibodies induced during the first dengue infection enhance infection of mononuclear cells during the second infection via cell surface FcγR (9, reviewed in 13). Thus, persistence of dengue-specific antibody may be a significant risk factor for development of severe disease in countries where dengue is hyperendemic.

We previously characterized an immunodomiant, HLA-A*0201 restricted, West Nile virus (WNV) peptide determinant. This dominant WNV peptide epitope, termed SVG9, lies within a highly conserved region of the envelope glycoprotein and demonstrates 100% homology among contemporary WNV strains. This region of the virus envelope is also highly conserved among other Flaviviruses such as Japanese encephalitis virus and Dengue virus (DV). Since immune cross reactivity has been reported within the Dengue virus serogroup, we hypothesized that T cells specific for this A*0201 restricted WNV stretch of envelope would cross-recognize different flaviviruses due to epitope conservation. As an initial test of this hypothesis we synthesized the corresponding envelope peptide for WNV (SVG9) and DV type 1 (SIG9). We utilized a competitive peptide binding assay to demonstrate that SVG9 and SIG9 have comparable and high A*0201 binding affinities. We then utilized PBMC from WNV and DV1 seropositive donors to assess T cell cross recognition of SVG9 and SIG9. T cells specific for the WNV SVG9 were cross-reactive for their DV1 Flaviviral counterpart SIG 9 and vice versa. These data demonstrate that cellular immunity is cross-reactive among different Flaviviruses. This observation has implications for vaccine development and for unraveling the immunopathology associated with infection.