MicroRNAs (miRNAs) are a class of small non-coding RNAs that are critical regulators of diverse biological processes. During biogenesis, the miRNA precursor undergoes sequential cleavage to liberate 21-22 nt RNA duplexes. Generally one of the two miRNA strands in the duplex is found in higher abundance in the cell. The low abundance or the “star” strand (miR*) has traditionally been assumed to be degraded; however, improved deep sequencing methods have shown that miRs* can be present at physiologically relevant levels. In this study, we found that both strands of the miR-8 duplex are present in high copy numbers suggesting that they may both be functional regulators. To investigate whether the miR* strand (miR-8-5p) impacts host-virus interactions, we challenged Drosophila melanogaster flies and cells with the natural Drosophila pathogen Drosophila C virus (DCV). We found that miR-8-5p is down-regulated in both systems by the presence of DCV. Using inhibitors that repress miR-8-5p, viral replication increased, indicating that the miR-8-5p modulates viral replication. To understand how miR-8-5p affects the host-virus interaction, we predicted its putative targets using bioinformatics. The predicted targets include Jun-related antigen (Jra), a homolog of mammalian cJun of the cJun NH2-terminal kinase (JNK) pathway. Jra was verified to be a target of synthetic miR-8-5p. During DCV infection, Jra is up-regulated, concomitant to miR-8-5p down-regulation. This is consistent with Jra being a target of miR-8-5p and with the involvement of this interaction in virus infection. To further confirm that miR-8-5p modulates DCV infection through regulation of Jra, we are now analyzing virus infection in Jra mutant flies. The results show the importance of the miR* strand in modulation of viral replication via targeting of host genes.