The host antiviral ribonuclease L protein supports Zika virus replication factory formation to enhance infectious virus production

Jillian N Whelan; Joshua Hatterschide; David M. Renner; Beihua Dong; Robert H Silverman; Susan R Weiss

The flavivirus Zika virus (ZIKV) activates ribonuclease L (RNase L) catalytic antiviral 26 function during infection, yet deletion of RNase L decreases ZIKV production, suggesting 27 a proviral role of RNase L. In this study, we reveal that latent RNase L supports ZIKV 28 replication factory (RF) assembly. Deletion of RNase L induced broader cellular 29 distribution of ZIKV dsRNA and NS3 compared with densely concentrated RFs detected 30 in WT cells. An inactive form of RNase L was sufficient to contain ZIKV genome and 31 dsRNA within a smaller area, which increased levels of viral RNA within RFs as well as 32 infectious ZIKV released from the cell. We used a microtubule stabilization drug to 33 demonstrate that RNase L deletion impaired the cytoskeleton rearrangements that are 34 required for proper generation of RFs. During infection with dengue or West Nile Kunjin 35 viruses, RNase L decreased virus production, suggesting that RNase L proviral function 36 is specific to ZIKV. report of viral resistance to catalytically active RNase L during infection, we sought to 113 isolate the differences between ZIKV RFs and those constructed by other flaviviruses, to 114 identify factors that enable this ZIKV evasion mechanism. 115 All rights reserved. No reuse allowed without permission.