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Yellow fever virus (YFV) is the prototypical hemorrhagic fever virus, yet our understanding of its phenotypic diversity and any molecular basis for observed differences in disease severity and epidemiology is lacking, when compared to other arthropod-borne and haemorrhagic fever viruses. This is, in part, due to the availability of safe and effective vaccines resulting in basic YFV research taking a back seat to those viruses for which no effective vaccine occurs. However, regular outbreaks occur in endemic areas, and the spread of the virus to new, previously unaffected, areas is possible. Analysis of isolates from endemic areas reveals a strong geographic association for major genotypes, and recent epidemics have demonstrated the emergence of novel sequence variants. This review aims to outline the current understanding of YFV genetic and phenotypic diversity and its sources, as well as the available animal models for characterizing these differences in vivo . The consequences of genetic diversity for detection and diagnosis of yellow fever and development of new vaccines and therapeutics are discussed. [ABSTRACT FROM AUTHOR]

Exploiting the inhibition of host signaling pathways aiming for discovery of potential antiflaviviral compounds is clearly a beneficial strategy for the control of life-threatening diseases caused by flaviviruses. Here we describe the antiviral activity of the MEK1/2 inhibitor U0126 against Yellow fever virus 17D vaccine strain (YFV-17D). Infection of VERO cells with YFV-17D stimulates ERK1/2 phosphorylation early during infection. Pharmacological inhibition of MEK1/2 through U0126 treatment of VERO cells blockades not only the YFV-stimulated ERK1/2 phosphorylation, but also inhibits YFV replication by ∼99%. U0126 was also effective against dengue virus (DENV-2 and -3) and Saint-Louis encephalitis virus (SLEV). Levels of NS4AB, as detected by immunofluorescence, are diminished upon treatment with the inhibitor, as well as the characteristic endoplasmic reticulum membrane invagination stimulated during the infection. Though not protective, treatment of YFV-infected, adult BALB/c mice with U0126 resulted in significant reduction of virus titers in brains. Collectively, our data suggest the potential targeting of the MEK1/2 kinase as a therapeutic tool against diseases caused by flaviviruses such as yellow fever, adverse events associated with yellow fever vaccination and dengue. [ABSTRACT FROM AUTHOR]

Abstract: A number of viruses in the family Flaviviridae are the focus of efforts to develop effective antiviral therapies. Success has been achieved with inhibitors for the treatment of hepatitis C, and there is interest in clinical trials of drugs against dengue fever. Antiviral therapies have also been evaluated in patients with Japanese encephalitis and West Nile encephalitis. However, no treatment has been developed against the prototype flavivirus, yellow fever virus (YFV). Despite the availability of the live, attenuated 17D vaccine, thousands of cases of YF continue to occur each year in Africa and South America, with a significant mortality rate. In addition, a small number of vaccinees develop severe systemic infections with the 17D virus. This paper reviews current efforts to develop antiviral therapies, either directly targeting the virus or blocking detrimental host responses to infection. [Copyright &y& Elsevier]

Abstract: Yellow fever virus (YFV) continues to cause outbreaks of disease in endemic areas where vaccine is underutilized. Due to the effectiveness of the vaccine, antiviral development solely for the treatment of YFV is not feasible, but antivirals that are effective in the treatment of related viral diseases may be characterized for potential use against YFV as a secondary indication disease. 2′-C-methylcytidine (2′-C-MeC), a compound active against hepatitis C virus, was found to have activity against the 17D vaccine strain of YFV in cell culture (EC90 =0.32μg/ml, SI=141). This compound was effective when added as late as 16h after virus challenge of Vero cells. When administered to YFV-infected hamsters 4h prior to virus challenge at a dose as low as 80mg/kg/d, 2′-C-MeC was effective in significantly improving survival and other disease parameters (weight change, serum ALT, and liver virus titers). Disease was improved when compound was administered beginning as late as 3 d post-virus infection. Broadly active antiviral compounds, such as 2′-C-MeC, represent potential for the development of compounds active against related viruses for the treatment of YFV. [Copyright &y& Elsevier]