Flaviviral Infections and Potential Targets for Antiviral Therapy

The family Flaviviridae includes human and animal pathogenic viruses of global importance, e.g. the human flaviviruses West-Nile virus (WNV), dengue virus (DENV), Japanese encephalitis virus (JEV), tick-borne encephalitis virus (TBEV) and yellow fever virus (JEV) as well as hepacivirus hepatitis C virus (HCV). This virus family was named after the jaundice occurring in course of YFV infection, the first identified virus of the Flaviviridae (Monath, 1987; Halstead, 1992). In humans infections with Flaviviridae may lead to fulminant, hemorrhagic diseaes [YFV, DENV and omsk hemorrhagic fever virus (OHFV)], viral encephalitis [JEV, TBEV, WNV, St. Louis encephalitis virus (SLEV)] or chronic hepatitis C, formerly referred to as non-A, non-B hepatitis (HCV) (Monath & Heinz, 1996; Rice, 1996). Viruses belonging to the third genus, pestivirus, infect only animals, leading to severe disease of the host, usually followed by death [bovine viral diarrhea virus (BVDV), classical swine fever virus (CSFV) and border disease virus (BDV)] (Nettelton & Entrican, 1995). The genus flavivirus consists of more than 70 species that are, on the basis of phylogenetic analyses, divided into 14 classes which in turn are grouped into three clusters: the mosquitoborne cluster, the tick-borne cluster and the non-vector cluster. All flaviviruses of human importance are mosquitoor tick-borne viruses. They enter through the skin by the bite of an infected arthropod, proliferating locally and spreading through the blood circulation and cross the blood-brain barrier and finally entering the central nervous system. This fact is important for further pathogenesis and unfavorable clinical outcome of the infection (King et al., 2007). Most pathogenic flaviviruses are associated with neurological diseases. The mosquito-borne encephalitic flaviviruses are grouped phylogenetically in the Japanese encephalitis serocomplex. Most tick-borne flaviviruses cause encephalitis and are mainly spread through Europe and Asia. Approximately up to 200 million new cases of infections caused by viruses of the Flaviviridae family are registered annually. Up to date, there is no effective antiviral therapy directed against Flaviviridae viruses. Members of the family of Flaviviridae are small (40 to 50 nm), spheric, enveloped RNA viruses of similar structure. The genome of the viruses consists of one single-stranded, positive-sense RNA with a length of 9100 to 11000 bases [e.g. 10862 for YFV (strain 17D), 10477 for Russian spring-summer encephalitis virus (RSSEV) and approx. 9100 for HCV].