Tick-borne encephalitis virus (TBEV) is a positive-strand RNA virus associated with tick-borne encephalitis in the genus Orthoflavivirus.

TBEV is a member of the genus Flavivirus. Other close relatives, members of the TBEV serocomplex, include Omsk hemorrhagic fever virus, Kyasanur Forest disease virus, Alkhurma virus, Louping ill virus and Langat virus.

TBEV has three subtypes:

The reference strain is the Sofjin strain.

TBEV is a positive-sense single-stranded RNA virus, contained in a 40-60 nm spherical, enveloped capsid. The TBEV genome is approximately 11kb in size, which contains a 5' cap, a single open reading frame with 3' and 5' UTRs, and is without polyadenylation. Like other flaviviruses, the TBEV genome codes for ten viral proteins, three structural, and seven nonstructural.

The structural proteins are C (capsid), PrM (premembrane), which is cleaved to produce the final membrane protein, (M), and envelope protein (E). The seven nonstructural proteins are: NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5. The role of some nonstructural proteins is known, NS5 serves as RNA-dependent RNA polymerase, NS3 has protease (in complex with NS2B) and helicase activity. Structural and nonstructural proteins are not required for the genome to be infectious. All viral proteins are expressed as a single large polyprotein, with the order C, PrM, E, NS1, NS2A, NS2B, NS3, NS4A, NS4B, NS5.

The envelope protein is involved in receptor-binding and neurovirulence, where increased glycosaminoglycan-binding affinity attenuates neuroinvasiveness. The conformation of the E protein during viral particle secretion is influenced by glycosylation as well. The immunogenicity of TBEV NS1 has been demonstrated, showcasing its ability to trigger oxidative stress and elicit the expression of immunoproteasome subunits. Additionally, it has been observed to stimulate the production of cytokines. The NS5 protein has interferon antagonist activity as it downregulates the expression of IFN receptor subunit. Non structural protein 5 (NS5) affects neuropathogenesis by attenuation of neurite outgrowth. Untranslated region 3 (UTR3) and UTR 5 affect genomic RNA cyclization and replication, and viral RNA transport in dendrites, which impacts neurogenesis and synaptic communication.

Infection of the vector begins when a tick takes a blood meal from an infected host. This can occur at any part of the tick's life cycle but a horizontal transmission between infected nymphs and uninfected larvae co-feeding on the same host is thought to be key in maintaining the circulation of TBEV. TBEV in the blood of the host infects the tick through the midgut, from where it can pass to the salivary glands to be passed to the next host. In non-adult ticks, TBEV is transmitted transtadially by infecting cells that are not destroyed during molting, thus the tick remains infectious throughout its life. Infected adult ticks may be able to lay eggs that are infected, transmitting the virus transovarially.