Abstract
An essential challenge in the lifecycle of RNA viruses is identifying and replicating the viral genome amongst all the RNAs present in the host cell cytoplasm. Yet, how the viral polymerase selectively recognizes and copies the viral RNA genome is poorly understood. In flaviviruses, the 5′-end of the viral RNA genome contains a 70 nucleotide-long stem-loop, called stem-loop A (SLA), which functions as a promoter for genome replication. During replication, flaviviral polymerase NS5 specifically recognizes SLA to both initiate viral RNA synthesis and to methylate the 5′ guanine cap of the nascent RNA. While the sequences of this region vary between different flaviviruses, the three-way junction arrangement of secondary structures is conserved in SLA, suggesting that viruses recognize a common structural feature to replicate the viral genome rather than a particular sequence. To better understand the molecular basis of genome recognition by flaviviruses, we recently determined the crystal structures of flavivirus SLAs from dengue virus (DENV) and Zika virus (ZIKV). In this review, I will provide an overview of (1) flaviviral genome replication; (2) structures of viral SLA promoters and NS5 polymerases; and (3) and describe our current model of how NS5 polymerases specifically recognize the SLA at the 5′ terminus of the viral genome to initiate RNA synthesis at the 3′ terminus.
Highlights
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Processing of the stem-loops in the 3 untranslated region (3 UTR) leads to generation of subgenomic flavivirus RNAs, which are involved in overall pathogenicity and evasion of the interferon response [9,10,11]
Flavivirus genome is suggested to exist in a linear form that is required for viral protein translation and in a circular form that is required for viral genome replication [6]
Summary
Flaviviruses are important human pathogens that are transmitted by mosquitoes or ticks. Members of flavivirus include dengue (DEN), Zika (ZIK), West Nile (WN), Japanese encephalitis (JE), yellow fever (YF) and tick-borne encephalitis viruses (TBEV), all of which cause wide-spread death and disease throughout the world. The incidence of DENV infection, caused by one of the four serotypes of DENV (DENV1-4), has increased dramatically in recent decades. The CDC estimates that up to 400 million people are infected with DENV; approximately 100 million people show symptoms, and 22,000 people die from severe dengue diseases [2]. Despite the significant impact of flavivirus infection on human health and looming threats of future flavivirus epidemics, vaccines are available only for a limited number of flaviviruses, and no antiviral therapies to treat viral infections are available for any flavivirus
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