Abstract
Most alphaviruses (family Togaviridae) including Sindbis virus (SINV) and other human pathogens, are transmitted by arthropods. The first open reading frame in their positive strand RNA genome encodes for the non-structural polyprotein, a precursor to four separate subunits of the replicase. The replicase interacts with cis-acting elements located near the intergenic region and at the ends of the viral RNA genome. A trans-replication assay was developed and used to analyse the template requirements for nine alphavirus replicases. Replicases of alphaviruses of the Semliki Forest virus complex were able to cross-utilize each other’s templates as well as those of outgroup alphaviruses. Templates of outgroup alphaviruses, including SINV and the mosquito-specific Eilat virus, were promiscuous; in contrast, their replicases displayed a limited capacity to use heterologous templates, especially in mosquito cells. The determinants important for efficient replication of template RNA were mapped to the 5' region of the genome. For SINV these include the extreme 5'- end of the genome and sequences corresponding to the first stem-loop structure in the 5' untranslated region. Mutations introduced in these elements drastically reduced infectivity of recombinant SINV genomes. The trans-replicase tools and approaches developed here can be instrumental in studying alphavirus recombination and evolution, but can also be applied to study other viruses such as picornaviruses, flaviviruses and coronaviruses.
Highlights
The genus Alphavirus comprises approximately 30 known virus species
Alphaviruses are positive-strand RNA viruses, most of which use mosquitoes to spread between vertebrate hosts; many are human pathogens with potentially severe medical consequences
Some alphavirus species are believed to have resulted from the recombination between different members of the genus and there is evidence of movement of alphaviruses between continents
Summary
The genus Alphavirus (family Togaviridae) comprises approximately 30 known virus species Many of these are “arboviruses”, infecting vertebrate hosts and are transmitted through the bite of an arthropod vector, commonly mosquitoes. Many alphaviruses present a threat to human health. These include chikungunya virus (CHIKV), which recently (re-)emerged in Asia, Africa and America [1], o’nyong-nyong virus (ONNV) that is widespread in Africa [2], Ross River virus (RRV) which is epidemic in Australia/Oceania [3] and Venezuelan equine encephalitis virus (VEEV) which is found in the Americas [4,5]. In addition to arboviruses there are horizontally transmitted alphaviruses such as salmon pancreas disease virus (salmonid alphavirus, SAV) infecting aquatic species Some alphaviruses, such as Eilat virus (EILV), lack a vertebrate host and infect arthropods exclusively [6,7]
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