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Open AccessArticle

Disruption of Zika Virus xrRNA1-Dependent sfRNA1 Production Results in Tissue-Specific Attenuated Viral Replication

Department of Immunology & Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Department of Biochemistry and Molecular Genetics and 4RNA BioScience Initiative, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA
Department of Medicine, Division of Infectious Diseases, University of Colorado School of Medicine, Aurora, CO 80045, USA
Rocky Mountain Regional VA Medical Center, Aurora, CO 80045, USA
Author to whom correspondence should be addressed.
Viruses 2020, 12(10), 1177;
Received: 10 September 2020 / Revised: 9 October 2020 / Accepted: 16 October 2020 / Published: 18 October 2020
(This article belongs to the Special Issue MicroRNAs and Other Small RNAs in Viral Infections)
The Zika virus (ZIKV), like other flaviviruses, produces several species of sub-genomic RNAs (sfRNAs) during infection, corresponding to noncoding RNA fragments of different lengths that result from the exonuclease degradation of the viral 3′ untranslated region (UTR). Over the course of infection, these sfRNAs accumulate in the cell as a result of an incomplete viral genome degradation of the 3′ UTR by the host 5′ to 3′ exoribonuclease, Xrn1. The halting of Xrn1 in the 3′ UTR is due to two RNA pseudoknot structures in the 3′ UTR, termed exoribonuclease-resistant RNA1 and 2 (xrRNA1&2). Studies with related flaviviruses have shown that sfRNAs are important for pathogenicity and inhibiting both mosquito and mammalian host defense mechanisms. However, these investigations have not included ZIKV and there is very limited data addressing how sfRNAs impact infection in a whole animal model or specific tissues. In this study, we generate a sfRNA1-deficient ZIKV (X1) by targeted mutation in the xrRNA1 3′ UTR structure. We find that the X1 virus lacks the production of the largest ZIKV sfRNA species, sfRNA1. Using the X1 virus to infect adult Ifnar1/ mice, we find that while the lack of sfRNA1 does not alter ZIKV replication in the spleen, there is a significant reduction of ZIKV genome replication in the brain and placenta compared to wild-type ZIKV infection. Despite the attenuated phenotype of the X1 ZIKV, mice develop a robust neutralizing antibody response. We conclude that the targeted disruption of xrRNA1 results in tissue-specific attenuation while still supporting robust neutralizing antibody responses. Future studies will need to investigate the tissue-specific mechanisms by which ZIKV sfRNAs influence infection and may utilize targeted xrRNA mutations to develop novel attenuated flavivirus vaccine approaches. View Full-Text
Keywords: Zika virus; flavivirus; RNA structure; non-coding RNA; replication; antibody Zika virus; flavivirus; RNA structure; non-coding RNA; replication; antibody
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Sparks, H.; Monogue, B.; Akiyama, B.; Kieft, J.; Beckham, J.D. Disruption of Zika Virus xrRNA1-Dependent sfRNA1 Production Results in Tissue-Specific Attenuated Viral Replication. Viruses 2020, 12, 1177.

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