Perspectives for the treatment of infections with Flaviviridae

Abstract

The family Flaviviridae contains three genera: Hepacivirus, Flavivirus, and Pestivirus. Worldwide, more than 170 million people are chronically infected with Hepatitis C virus and are at risk of developing cirrhosis and/or liver cancer. In addition, infections with arthropod-borne flaviviruses (such as dengue fever, Japanese encephalitis, tick-borne encephalitis, St. Louis encephalitis, Murray Valley encephalitis, West Nile, and yellow fever viruses) are emerging throughout the world. The pestiviruses have a serious impact on livestock. Unfortunately, no specific antiviral therapy is available for the treatment or the prevention of infections with members of the Flaviviridae. Ongoing research has identified possible targets for inhibition, including binding of the virus to the cell, uptake of the virus into the cell, the internal ribosome entry site of hepaciviruses and pestiviruses, the capping mechanism of flaviviruses, the viral proteases, the viral RNA-dependent RNA polymerase, and the viral helicase. In light of recent developments, the prevalence of infections caused by these viruses, the disease spectrum, and the impact of infections, different strategies that could be pursued to specifically inhibit viral targets and animal models that are available to study the pathogenesis and antiviral strategies are reviewed.

FIG. 1

Genomic organization of members of the Flaviviridae. The viral genome consists of a single-stranded RNA molecule of positive polarity which is capped in flaviviruses and contains an IRES in hepaciviruses and pestiviruses. UTR are present at the 5′ and 3′ ends of the genome. Boxes indicate mature proteins generated by proteolytic processing.

FIG. 2

Replicative cycle of members of the Flaviviridae. The presumed replication cycles of the hepaciviruses and pestiviruses (A) and of the flaviviruses (B) are shown. 1, adsorption; 2, receptor-mediated endocytosis; 3, low-pH fusion in lysosomes; 4, uncoating; 5, IRES-mediated initiation of translation (A) or cap-mediated initiation of translation (B); 6, translation of the viral RNA into viral precursor polyprotein; 7, co- and posttranslational proteolytic processing of the viral polyprotein by cellular and viral proteases; 8, membrane-associated synthesis of template minus-strand RNA and progeny plus-strand RNA; 9, assembly of the nucleocapside; 10, budding of virions in the endoplasmatic reticulum; 11, transport and maturation of virions in the endoplasmatic reticulum and the Golgi complex; 12, vesicle fusion and release of mature virions. ss, single stranded.