Alphaviruses optimize viral polymerase production and polyprotein processing at distinct temperatures via a premature stop codon.

Mosquito-transmitted alphaviruses, including chikungunya (CHIKV), Mayaro, Eastern equine encephalitis, and Venezuelan equine encephalitis viruses, cause severe arthritic or neurologic disease in humans. There are currently no approved antiviral treatments against alphavirus infection. Here, we report that the purine ribonucleoside EIDD-3525 is a potent inhibitor of alphavirus replication in vitro with broad spectrum antiviral activity against the Alphavirus genus. Using a trans-replicase assay, we find that EIDD-3525 blocks alphavirus RNA replication. Mutational profiling suggests that EIDD-3525 targets the alphavirus nsP4 RNA-dependent RNA polymerase that is conserved across medically important alphaviruses. In a pre-clinical mouse model of CHIKV infection and disease, oral treatment with EIDD-3525 reduced viral tissue burdens and the severity of virus-induced disease. Collectively, our findings support the continued development of the purine ribonucleoside EIDD-3525 as an orally available antiviral therapeutic for use against a broad group of alphaviruses.

Most alphaviruses encode an in-frame opal stop codon between nsP3 and nsP4 in their nsP ORF. This opal stop codon mediates a temperature-dependent balance between viral polymerase production and prote...

Diagnóstico Clínico Laboratorial da Chikungunya A febre Chikungunya, arbovirose causada por um vírus do gênero Alphavirus e transmitida pe...

Alphaviruses are enveloped, positive-sense RNA viruses in the Togaviridae family and Alphavirus genus (1, 2). They are transmitted mainly by mosquitoes, which become infected while feeding on a viremic vertebrate host and later transmit the virus during subsequent blood meals (3). For a successful transmission cycle, the virus must replicate in both the mosquito and the vertebrate host. Alphaviruses infect a broad range of vertebrates, including humans, other mammals, birds, fish, and reptiles (4, 5). Their emergence, defined as the first appearance or spread into new regions, and reemergence, a resurgence after a period of decline (6), pose an increasing threat to public and animal health, as well as a substantial economic burden (7, 8). Alphaviruses are classified by the type of disease caused. Encephalitic alphaviruses include Venezuelan, western, and eastern equine encephalitis viruses (VEEV, WEEV, and EEEV). Arthritogenic alphaviruses include Chikungunya virus (CHIKV), o'nyong-nyong virus (ONNV), and Ross River virus (RRV) (1), among others.

Xie and Cao et al. show that nsP3-FXR condensation is crucial for VEEV replication. UBAP2L is identified as a nsP3-FRX condensate-resident restriction factor that suppresses VEEV replication. Targeting conserved nsP3 AUD via RING-bait technology offers a broad-spectrum antiviral strategy against multiple alphaviruses.

Bats are reservoirs for many viruses that frequently cause epidemics in humans and animals. It is thus critical to better understand their immune system and mechanisms of antiviral immunity. Despite a...