General Classification and Structure
The family name derives from the Latin word flavus (yellow), named after the type species, Yellow fever virus. Human pathogens are divided into two main genera:
- Genus Flavivirus. Includes classic arboviruses maintained in nature by arthropod vectors (Yellow fever, dengue, tick-borne encephalitis, and Japanese encephalitis viruses).
- Genus Hepacivirus. Comprises agents of parenteral viral hepatitis (Hepatitis C and G viruses). Notably, hepaciviruses are not arboviruses.
Virions are spherical and small in size (40–60 nm). They are enveloped viruses characterized by:
- Genome: A linear single-stranded +RNA molecule.
- Capsid: Icosahedral symmetry composed of the C protein.
- Envelope: An outer lipoprotein membrane surrounding the capsid. It contains two key elements: the structural M protein and the surface glycoprotein E.
Antigenic Properties and Replication
The primary antigen is glycoprotein E. It carries species- and genus-specific determinants and exhibits hemagglutinating properties active only within a narrow pH range. Infected cells also produce a soluble antigen active in complement fixation tests (CFT) and capable of inducing neutralizing antibodies.
Viral entry into the host cell occurs via receptor-mediated endocytosis: the virus binds to surface phospholipids and glycolipids, and uncoating occurs upon fusion of the viral envelope with the endosomal membrane.
Genomic RNA with a sedimentation coefficient of 45 S is synthesized inside the infected cell. A distinctive feature of flaviviruses is that their replication complex is closely associated with the nuclear membrane (unlike alphaviruses, which localize to endoplasmic reticulum membranes). Virions mature by budding through endoplasmic reticulum membranes, forming characteristic crystal-like aggregates within vacuolar spaces.
Epidemiological Features
Flavivirus infections are widespread in nature and represent classic zoonotic, vector-borne diseases. The primary reservoirs and vectors are blood-feeding arthropods. Viruses persist in insect and tick populations through two main mechanisms:
- Transstadial transmission (pathogen persists through larval, nymphal, and adult stages).
- Transovarial transmission (from infected females through eggs to their offspring).
Diseases are broadly divided into mosquito-borne and tick-borne. Mosquito-borne infections (dengue fever, yellow fever, Japanese encephalitis) occur predominantly in southern and tropical latitudes. Tick-borne infections (tick-borne encephalitis, Omsk hemorrhagic fever) are widely distributed.
Vertebrate animals (rodents, birds, primates, bats) serve as amplifying hosts: they carry the infection asymptomatically with high levels of viremia, infecting new vectors. Humans typically act as "dead-end" hosts in this chain, with the exception of urban epidemics of dengue and yellow fever, where humans can serve as a reservoir.
Cultivation and Diagnostic Methods
Three primary biological models are used for viral isolation: cell cultures (SPEV, BHK-21), animal bioassays in mice, and embryonated chicken eggs. In warm-blooded cell cultures, viruses induce a mild cytopathic effect (CPE), whereas in arthropod cells they replicate without CPE. Intracerebral inoculation in mice results in paralysis.
Microbiological diagnostics include:
- Serological testing: Analysis of paired sera. Recent infection is indicated by the appearance of immunoglobulin M (IgM) or a $\ge$4-fold rise in antibody titer (measured by HI, CFT, or ELISA). The most specific test for differentiating closely related viruses is the neutralization test (NT).
- Virological testing: Isolation of the pathogen from blood, cerebrospinal fluid (especially in encephalitis cases), autopsy material, or environmental vectors.
- Molecular genetics: Detection of viral RNA via RT-PCR.
Antiviral therapy includes antiviral agents (ribavirin, interferons) and immunoglobulins. Specific prophylaxis is achieved using killed (formalin-inactivated) vaccines, with the exception of the live-attenuated yellow fever vaccine. Virions are relatively unstable in the environment and are rapidly inactivated by formalin and lipid solvents (ether) due to their lipid envelope.