Alphaviruses, belonging to the Togaviridae family, are enveloped, single-stranded, positive-sense RNA viruses with a genome approximately 11-12 kb in length. This genome encodes two polyproteins: the non-structural polyprotein (nsP1-4), responsible for viral replication and transcription, and the structural polyprotein (C-E3-E2-6K-E1-TF), which forms the viral capsid and envelope. Chikungunya virus (CHIKV), eastern equine encephalitis virus (EEEV), venezuelan equine encephalitis virus (VEEV), and western equine encephalitis virus (WEEV) are prominent members, each exhibiting unique molecular adaptations.
The structural proteins include the capsid protein (C) and envelope glycoproteins (E1, E2, E3, and 6K), along with the transframe (TF) protein. E1 and E2 are critical for viral entry, mediating membrane fusion and receptor binding, respectively, while E3 acts as a chaperone during protein folding. The 6K protein, and its derivative TF, contribute to virion assembly and budding. CHIKV is notable for its E1-E2 heterodimer stability, enhancing its transmission by Aedes mosquitoes. EEEV, VEEV, and WEEV, primarily transmitted by Culiseta or Culex mosquitoes, share a similar glycoprotein arrangement but differ in nsP mutations that influence replication efficiency and host specificity.
The non-structural proteins (nsP1-4) form the replication complex, with nsP1 involved in capping, nsP2 in RNA helicase and protease activities, nsP3 in RNA binding, and nsP4 as the RNA-dependent RNA polymerase. These proteins' interactions and post-translational modifications, such as phosphorylation, regulate the switch from negative-strand to positive-strand RNA synthesis, a key molecular feature of alphavirus replication. This molecular machinery underlies the pathogens' ability to cause diseases ranging from arthralgia (CHIKV) to severe encephalitis (EEEV, VEEV, WEEV).