Zika Virus Subgenomic Flavivirus RNA Generation Requires Cooperativity between Duplicated RNA Structures That Are Essential for Productive Infection in Human Cells

Zika virus (ZIKV) is an emerging flavivirus, mainly transmitted by mosqui-toes, which represents a global health threat. A common feature of flavivirus-infected cells is the accumulation of viral noncoding subgenomic RNAs by partial degradation of the viral genome, known as sfRNAs, involved in immun...

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Veröffentlicht in:Journal of virology 2020-08, Vol.94 (18), Article 00343
Hauptverfasser: Pallares, Horacio M., Navarro, Guadalupe Soledad Costa, Villordo, Sergio M., Merwaiss, Fernando, de Borba, Luana, Ledesma, Maria M. Gonzalez Lopez, Ojeda, Diego S., Henrion-Lacritick, Annabelle, Morales, Maria A., Fabri, Cintia, Saleh, Maria Carla, Gamarnik, Andrea V.
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Sprache:eng
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Zusammenfassung:Zika virus (ZIKV) is an emerging flavivirus, mainly transmitted by mosqui-toes, which represents a global health threat. A common feature of flavivirus-infected cells is the accumulation of viral noncoding subgenomic RNAs by partial degradation of the viral genome, known as sfRNAs, involved in immune evasion and pathogenesis. Al-though great effort is being made to understand the mechanism by which these sfRNAs function during infection, the picture of how they work is still incomplete. In this study, we developed new genetic tools to dissect the functions of ZIKV RNA structures for viral replication and sfRNA production in mosquito and human hosts. ZIKV infections mostly accumulate two kinds of sfRNAs, sfRNA1 and sfRNA2, by stalling genome degradation upstream of duplicated stem loops (SLI and SLII) of the viral 3' untranslated region (UTR). Although the two SLs share conserved sequences and structures, different func-tions have been found for ZIKV replication in human and mosquito cells. While both SLs are enhancers for viral infection in human cells, they play opposite roles in the mosquito host. The dissection of determinants for sfRNA formation indicated a strong cooperativ-ity between SLI and SLII, supporting a high-order organization of this region of the 3' UTR. Using recombinant ZIKV with different SLI and SLII arrangements, which produce different types of sfRNAs or lack the ability to generate these molecules, revealed that at least one sfRNA was necessary for efficient infection and transmission in Aedes aegypti mosquitoes. Importantly, we demonstrate an absolute requirement of sfRNAs for ZIKV propagation in human cells. In this regard, viruses lacking sfRNAs, constructed by dele-tion of the region containing SLI and SLII, were able to infect human cells but the infec-tion was rapidly cleared by antiviral responses. Our findings are unique for ZIKV, since in previous studies, other flaviviruses with deletions of analogous regions of the genome, including dengue and West Nile viruses, accumulated distinct species of sfRNAs and were infectious in human cells. We conclude that flaviviruses share common strategies for sfRNA generation, but they have evolved mechanisms to produce different kinds of these RNAs to accomplish virus-specific functions. IMPORTANCE Flaviviruses are important emerging and reemerging human patho-gens. Understanding the molecular mechanisms for viral replication and evasion of host antiviral responses is relevant to developm
ISSN:0022-538X
1098-5514
DOI:10.1128/JVI.00343-20