The family Flaviviridae includes four genera (Table 29.1), one of which is designated Flavivirus. In an effort to avoid confusion in this chapter, the term “flavivirus” will be applied only to members of the genus Flavivirus unless otherwise specified, and not to member viruses of the three other genera in the family (which will be designated individually as pestiviruses, hepaciviruses, or pegiviruses).

All members of the genus Flavivirus are closely related and share significant amino acid sequence identity, which results in serological cross-reactivity. Historically, members of this genus were assigned to it on the basis of these antigenic cross-reactions. Since most of the viruses are transmitted by arthropods (vector-borne), they were once referred to as Group B arboviruses. These vector-borne flaviviruses are divided into two major groups based on the vector they utilize for transmission: the mosquito-borne flaviviruses (including yellow fever virus, dengue virus complex, and Japanese encephalitis complex viruses) and the tick-borne encephalitis (TBE) group of flaviviruses (Table 29.1). A third group of flaviviruses are either not vector-borne or have an as yet unidentified arthropod vector [eg, Apoi virus (rodent virus), Israel turkey meningoencephalitis virus, and Rio Bravo (bat virus)], and a fourth group of flaviviruses have no known natural animal host. Most of the approximately 90 known flaviviruses are transmitted by mosquitoes, but at least 14 are transmitted by ticks, generally Ixodid species. Individual flaviviruses are adapted to either a tick or mosquito vector, and interchange of vectors does not occur. Furthermore, the mosquito-borne flaviviruses segregate phylogenetically into a lineage vectored primarily by mosquitoes belonging to the genus Culex and virus lineages vectored by mosquitoes belonging to the genus Aedes. However, in each of these lineages the restriction on the species of mosquito vector is not firm and mosquitoes belonging to other genera may also vector many of these viruses (eg, yellow fever virus in Africa is vectored by Aedes mosquitoes whereas in the Americas it is vectored by Hemagogous mosquitoes). The mosquito- and tick-borne flaviviruses are maintained in nature within arthropod–vertebrate–arthropod cycles, whereas the nonarthropod-borne viruses presumably are transmitted directly among their bat or rodent hosts.

Genomic sequence analyses confirm that the principal pestiviruses, ie, bovine virus diarrhea virus (with two different genotypes designated 1 and 2), Border disease virus, and classical swine fever virus, are closely related (Fig. 29.1). Pestiviruses also have an overlapping host spectrum, but with species-specific preferences: swine fever virus can be transmitted to cattle; bovine viral diarrhea virus can infect swine, sheep, goats, New World camelids, and a variety of other wild and domestic ungulates, including deer, antelope, yak, and buffalo; border disease virus infection rarely has been documented in cattle. Variant pestiviruses have been identified in giraffe, swine (Bungowannah virus—Australia; atypical porcine pestivirus—US), bats, and cattle (“Hobi-like” atypical pestiviruses).

The genus Hepacivirus contains human hepatitis C virus, the cause of hepatitis C, and similar viruses of horses and other nonprimate species. Other human viruses (so-called “GB viruses”) in the family that were initially included in the genus Hepacivirus, but which are not associated with severe liver disease are now reclassified in the genus Pegivirus, along with related viruses from animals (eg, horses, nonhuman primates, bats, and rodents).

Virions of viruses in the family Flaviviridae, regardless of genus, are spherical, 50 nm (flaviviruses, hepaciviruses) or 40–60 nm (pestiviruses) in diameter, and consist of a tightly adherent lipid envelope that may display indistinct glycoprotein spikes, surrounding a spherical nucleocapsid with icosahedral symmetry (Fig. 29.2; Table 29.2). The genome consists of a single molecule of linear, positive-sense, single-stranded RNA of approximately 11, 12.3, 9.6–10.4 kb, and 11.2 kb for flavi-, pesti-, hepaci-, and pegiviruses, respectively. Flaviviruses have a 5′-terminal cap structure, whereas pestiviruses, hepaciviruses, and pegiviruses do not. Instead of the 5′ cap, the hepaci-, pesti-, and pegiviruses have an internal ribosomal entry site in the 5′ nontranslated region. Member viruses of the family Flaviviridae do not have a poly-A tail at the 3′-end of the genome.

The genome of all members of the family contains one long open reading frame encoding 10 or more proteins that are created by co- and posttranslational processing and cleavage of a single, large polyprotein (Fig. 29.3). Virions contain three (genera Flavivirus, Hepacivirus, and Pegivirus) or four (genus Pestivirus) structural proteins that are encoded in the 5′ end of the genome; the nonstructural proteins are encoded in the 3′ end. Structural proteins of flaviviruses include: C, the nucleocapsid protein; prM, a precursor glycoprotein that is cleaved during virus maturation to yield M, the transmembrane protein; E, the major spike glycoprotein, which also is the major target for neutralizing antibodies. Pestiviruses have four structural proteins, including C (nucleocapsid protein) and the Erns, E1, and E2 envelope glycoproteins. There are seven or eight virus-encoded nonstructural proteins, including NS5, the RNA-dependent RNA polymerase, and NS3, which has several functions, including helicase and protease activities, in addition to contributing to the RNA polymerase complex. NS2B and NS3 are largely responsible for cleavage of the polyprotein, and host-cell proteases are responsible for the remainder of this processing. Flaviviruses encode only the NS3 protease, and the hepaci- and pestiviruses encode a second protease in the NS2 region that cleaves between NS2 and NS3. Pestiviruses also encode a unique nonstructural protein, Npro, which autocatalytically releases itself from the polyprotein; this protein is not essential for virus replication in cell culture, but modulates the interferon response in infected cells (see Chapter 4: Antiviral Immunity and Virus Vaccines).

Virus replication involves the synthesis of complementary negative-sense RNA, which then serves as a template for positive-sense (genome-sense) RNA synthesis. The only viral mRNA is the genomic RNA—translation yields a single polyprotein that is cleaved and processed to form the various structural and nonstructural virus proteins (Fig. 29.3). For mosquito-transmitted flaviviruses, virion assembly, including acquisition of the glycoprotein-containing lipid envelope, occurs on membranes of the endoplasmic reticulum and plasma membrane in mosquito cells (Fig. 29.4), but preformed capsids and budding are not seen. Instead, fully formed virions appear within the cisternae of the endoplasmic reticulum and are transported in cytoplasmic vesicles through the secretory pathway before they are released by exocytosis or cell lysis. West Nile virus is an exception to this general rule as there is prominent budding of preassembled nucleocapsid at the plasma membrane, although some intracellular assembly of virions also occurs.

Japanese encephalitis virus is an important mosquito-borne human pathogen in much of Asia including Southeast Asia, China, Japan, the Korean peninsula and adjacent areas of the Russian Federation, Sri Lanka, and portions of the Indian subcontinent with recent incursions into the Pacific islands and northern Australia (Fig. 29.5). Although there is a single serotype of Japanese encephalitis virus, at least five distinct genotypes (I–V) are recognized that differ in their regional and temporal distribution. Human disease is devastating. Although there are many inapparent infections, the case-fatality rate amongst symptomatic cases is 10–40%, and 40–70% of survivors have permanent neurologic deficits. The primary mosquito vector, Culex tritaeniorhynchus, develops in freshwater marshes and irrigated rice fields, and blood-feeds mostly on large mammals including, swine, and occasionally humans (Fig. 29.6). Japanese encephalitis virus also can be transmitted by Culex and Aedes mosquitoes. A variety of animals, including swine, horses, dogs, bats, and reptiles, are infected naturally with Japanese encephalitis virus. Horses may develop fatal encephalitis similar to that caused by West Nile virus infection, whereas infection of adult swine is generally inapparent, with the notable exception of the occurrence of stillbirths and abortion that may occur after infection of pregnant sows. Piglets may develop neuroinvasive disease.

Stay updated, free articles. Join our Telegram channel

Join