Hsiao, W.-Y.; Yeh, C.-S.; Liu, H.-I.; Tung, L.; Chang, T.-H.

Viruses are often regarded as obligate intracellular parasites that exploit host resources for their own propagation. However, emerging evidence suggests that virus-host interactions can be more complex than simple antagonism. Here, we performed a genome-wide screen in Saccharomyces cerevisiae to identify host factors required for the maintenance of the L-A double-stranded RNA virus, a persistent and non-lytic resident of most laboratory yeast strains. Using two complementary mutant collections encompassing ~6,000 yeast genes (~93% genome coverage), we identified 96 host genes essential for L-A maintenance, spanning diverse biological functions. Transcriptome profiling revealed that the presence of L-A virus alters the host stress-response gene expression program. Strikingly, competitive fitness assays under environmental stress conditions showed that L-A enhances host stress tolerance, revealing a previously unrecognized mutualistic relationship. Together, our findings redefine the L-A-yeast interaction as a form of stable mutualism and highlight the utility of functional genomics and systems-level approaches in uncovering hidden dimensions of virus-host coevolution.