Properties of Flaviviridae

Flavivirus virions are spherical, 40-50 nm in diameter, and consist of an inner viral core within a tightly adherent lipid envelope covered with glycoprotein peplomers (Fig. 26-1). The genome is a single linear 11 kb molecule of ssRNA of positive polarily which is 5' capped but not 3' polyadenylated, and is infectious. Other properties are summarized in Table 26-1.

Flaviviruses are not very stable in the environment and are easily inactivated by heat and by disinfectants containing detergents or lipid solvents.

Classification

There are no antigens shared between genera. Members of the genus Flavivirus have been grouped by neutralization tests into nine serogroups, each containing between three and ten members, with an additional 17 viruses currently unassigned to a group.

Viral Replication

Flaviviruses enter cells via receptor-mediated endocytosis, and replication takes place in the cytoplasm and is accompanied by proliferation of rough and smooth endoplasmic reticulum. The incoming genomic RNA serves directly as messenger; it contains one large open reading frame of over 10 kb and is translated completely from its 5' end to produce one large precursor polypro-tein which is then cleaved to produce individual viral proteins (Fig. 26-2). About one-quarter of the length of the genomic RNA from the 5' end encodes the three structural proteins: C, the core protein; prM, a precursor which is cleaved during virus maturation to yield M, the small transmembrane protein; and E, the major peplomer glycoprotein. The rest of the genome encodes seven nonstructural proteins, the functions of most of which are not fully understood; NS3 and NS5 are believed to form the RNA-dependent RNA

Fig. 26-1 Flavivtridae, genus rimrivirus. Negatively stained virions of tick-home encephalitis virus Bar, 100 nm. (Courtesy Drs W. Tuma, F X. Heinz, and C. Kunz.)

Table 26-1

Properties of FJaviviruses

Genera- Flmnvirnii, mostly arthropod-borne viruses, Hcpalil/*, C, human hepatitis C virus

Sphcrical virion, enveloped, diameter 40-50 rim, envelope containing peplomers (glycoprotein E) and small membrane protein (M)

Inner core, 30 nm, composed of core protein (C)

Linear plus sense ssRNA genome, 10 5-11 kb (9 5 kb for hepatitis C virus), 5' capped, 3' usually not polyadenylated but looped, infectious

Genes for structural proteins located at 5' end of genome, those for nonstructural proteins at 3' end

Cytoplasmic replication, polyprotein translated from genomic RNA cotranslafionally cleaved to yield several nonstructural proteins and three structural proteins; maturation into cytoplasmic vesicles polymerase complex, with NS5 carrying replicase activity and NS3 possessing both helicase and protease activities. NS3 is responsible for most of the co-translational cleavage of the portion of the nascent polyprotein that yields the nonstructural proteins, whereas cellular signal peptidase effects the other primary cleavages.

Replication of the genome occurs in perinuclear foci and involves the synthesis of a complementary minus strand, which in turn serves as template for the synthesis of more plus strand molecules. During infection, plus strand synthesis is favored, suggesting complex regulatory mechanisms which appear to involve host cell constituents. Virion assembly occurs in vertebrate cells on membranes of the endoplasmic reticulum and in mosquito cells on the plasma membrane also, but preformed capsids and budding are not seen. Instead, fully formed virions appear within cisternae of the endoplasmic reticulum and are released via cell lysis. The latent period is long (12 hours or more), and virus production from any given cell continues for days without shutdown of cellular nucleic acid or protein synthesis. Some flaviviruses induce syncytia or plaques in monolayer cultures of mammalian cells, but non-cytocidai persistent infections commonly occur in invertebrate cells.

cap virion proteins | nonstructural proteins cotranslational processing

~ NS2A NS2B NS4A NS4B

I Golgi protease

Pr "Ml

Fig. 26-2 Structure and translation of the flavivirus genome The regions of the genome encoding the structural and nonstructural proteins are shown in the box at top, the RNA is capped at the 5' end but is not polyadenylated There are shorl nontranslated sequences at each terminus (single lines) The genome is the only mRNA and is translated into a single polyprotein which is cotranslationally cleaved by viral and cellular proteases to form Ihe structural proteins C, M, and E and seven nonstiuctural proteins.

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