Experimental therapies for yellow fever

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.

Figure 1

A graphical representation of the flavivirus genome. The structural capsid (C), premembrane (prM), and envelope proteins are situated at the 5′ end of the translated region. The nonstructural (NS) proteins 1, 2A, 2B, 3, 4A, 4B, and 5 are located at the 3′ end of the genome. The 3′ and 5′ terminal ends possess untranslated regions (UTR) that are important for replication. The 5′ end possesses a cap structure. Arrowheads represent host protease cleavage sites, while diamonds represent viral protease cleavage sites. Known functions of the various viral proteins are also included.

Figure 2

Replication strategy of the flaviviruses, including YFV. The virus enters the cell by endocytosis and the viral RNA is released following fusion with an endosome. Viral RNA is translated by host ribosomes into a single polyprotein that is processed by host and virus-encoded proteases. The nonstructural proteins are involved in replication of the viral RNA. Viral RNA and structural proteins are packaged together into progeny virions, which bud from internal membranes before being released from the cell. “Lightning bolts” indicate potential targets for antiviral intervention; details of each target are contained in the text.