Antiviral therapies are urgently needed to control emerging flaviviruses such as dengue, West Nile, and yellow fever. Ribavirin (RBV) has shown activity against flaviviruses in cultured cells, but efficacy in animal models has generally been poor. In a preliminary screen of novel, synthetic 1-β-D-ribofuranosyl-azole analogs, two compounds, 1-β-D-ribofuranosyl-3-ethynyl-[1,2,4]triazole (ETAR) and 1-β-D-ribofuranosyl-4-ethynyl [1,3]imidazole (IM18), significantly reduced replication of dengue virus serotype 2 (DENV-2) in cultured Vero cells. In the current study we demonstrated that the effective concentration 50 (EC 50 ) of ETAR for DENV-2 is substantially lower than both IM18 and RBV. Moreover ETAR reduced the replication of five additional flaviviruses, including DENV serotypes 1, 3 and 4, Langat virus and Modoc virus, ≥ 1000-fold relative to untreated controls. Addition of exogenous guanosine to DENV-2 infected cells negated the antiviral effects of both RBV and ETAR, indicating that GTP depletion is a major mechanism of action for both drugs. ETAR represents a promising drug candidate for treatment of flavivirus infections.

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Type I Interferon (IFN-α/β) is an innate cytokine important for fighting infections and is used to treat hepatitis C infection and multiple sclerosis, among other diseases. Although the innate role of this cytokine has been studied extensively, our group has shown that IFN-α/β plays a role in shaping the adaptive immune response in humans. Recently, we demonstrated that IFN-α/β inhibits Th2 development by regulating mRNA and protein levels of GATA3. Regulation of GATA3 in turn suppresses Th2 cytokine production, without effecting IFN-γ production. In addition to blocking Th2 development, we now demonstrate an acute inhibition of human memory T cell function upon treatment with IFN-α/β. Human memory CD4+ T cells acutely activated with anti-CD3 in the presence of IFN-α/β resulted in reduced mRNA levels of Th2 cytokine genes, IL5 and IL13, but did not effect IL4 expression. GATA3 levels were not affected, suggesting a GATA3-independent mechanism. Further experiments have determined that this regulatory mechanism does not require new protein synthesis. This mechanism seems to be specific to IFN-α/β, as neither IFN-γ nor IFN-λ treatment were able to repress Th2 cytokine mRNA expression to the extent of IFN-α/β. This study has uncovered an additional level of regulation that blocks early TCR signaling events that affect Th2 function. This novel pathway suggests that treatment of atopic asthmatic individuals with IFN-α/β can regulate both Th2 development and memory Th2 function.

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