Zika virus RNA structures act cooperatively to regulate the production of viral non-coding RNAs with different impact in mosquito and human hosts

PALLARÉS, HM; VILLORDO, S; GONZALEZ LOPEZ LEDESMA, MM; DE BORBA, L; HENRION-LACRITICK, A; GAMARNIK, ANDREA V.; COSTA NAVARRO, GS; MERIWAS, F; SALEH, MC

Fort Collins, Colorado

Congreso; 39th Annual Meeting of the American Society for Virology (ASV 2020); 2020

American Society for Virology

The explosive epidemic of Zika virus (ZIKV), together with the unique properties of this virus regardingtransmission and disease, posed a tremendous challenge to understand themolecular processes that lead to infection and pathogenesis.  ZIKV is an enveloped RNA virus, member of theFlaviviridae family, together with other important human pathogens transmittedby mosquitoes, such as dengue and yellow fever. In order to dissectfunctions and mechanisms of viral RNA structures during ZIKV infection, weconstructed infectious clones and reporter viruses from local Argentineanisolates. Using these tools, we analyzed the role of each 3?UTR element andfound a domain comprised by two stem loops (SL1 and SL2) that was essential forinfection in human cells. Surprisingly, a virus lacking this domain was able toinfect and propagate in mosquitoes and mosquito cells.  We studied the mechanisms by which the virusdisplayed different host restrictions and found the absolute requirement of accumulationof non-coding viral RNAs, known as sfRNAs, in human cells. The sfRNAs have beenpreviously involved in evasion of antiviral responses and are products ofpartial degradation of the viral genome. Construction of a battery of recombinantviruses tested in adult Ae aegyptimosquitoes and human cells indicated that SL1 and SL2 function in a cooperativemanner to generate sfRNAs. In this regard, the presence of SL2 was found to be essentialfor SL1 function. Our results support a model in which the two RNA elements atthe ZIKV 3?UTR control both sfRNAs production and differential replication in thetwo hosts. These findings are unique for ZIKV, because even though the SLdomain modulates differential host replication in other flaviviruses, only inZIKV the function is essential for productive infection in human cells. Thiswork provides new ideas regarding the impact of 3?UTR elements on hostadaptation, with possible implications in viral transmission.