Potato leafroll virus (PLRV), vectored by the green peach aphid, Myzus persicae, is a polerovirus causing significant economic damage in global potato production. PLRV infection results in stunting, leaf rolling, and net necrosis on tubers, threatening global cultivation, especially in regions with limited vector management options. Management relies on neonicotinoid insecticides, though increasing regulatory constraints and resistance in vector populations demand the development of alternative tactics. To address this need, I applied a systems-level analysis of host, viral proteins, aphid biology, and microbial interactions that influence virus transmission. I then leveraged these insights to design novel virus management strategies.The green peach aphid functions as a holobiont, encompassing both aphid-associated microorganisms and plant pathogenic viruses. I explored ideas to address the pressing need for aphid and PLRV management by targeting interactions within the holobiont. I then delved into PLRV’s impact on the aphid holobiont and highlighted literature showing the evolutionary and mechanistic ways in which PLRV influences the holobiont during plant infection. In plants, posttranscriptional gene silencing (PTGS) acts a targeted antiviral defense mechanism, which PLRV suppresses using the P0 protein. P0 not only inhibits PTGS in plants but also suppresses aphid immunity against the aphid-infecting virus, Myzus persicae densovirus (MpDNV). Plant expression of P0 independent of PLRV increases MpDNV titer in aphids and enhances aphid fecundity. By generating mutants of the F-box motif critical for P0 function, I demonstrated that the activity of P0 on aphid biology is dependent on functional P0 activity. Further, I showed that additional viral proteins from other plant viruses modulate MpDNV and fecundity, suggesting that aphid RNAi pathways are finely tuned to plant RNAi pathways, independent of vector capabilities and transmission. This work reveals the molecular mechanisms underpinning vector manipulation expected to promote the spread of plant viruses in nature. To dissect aphid-borne transmission, our collaborative group previously solved the 3-D structure of the N-terminal domain of the polerovirus readthrough protein, referred to as the NRTD, for PLRV and the related Turnip yellows virus. Laboratory transmission assays showed that transgenic potato plants expressing the NRTD reduce PLRV acquisition and transmission. To test whether NRTD transgenic plant technology can be scaled to field application, we conducted two years of greenhouse experiments using mass release of thousands of PLRV-viruliferous aphids with NRTD plants as border rows or intercropped with non-transgenic plants. The NRTD plants reduce aphid movement, PLRV transmission, PLRV titer in aphids, and alter the titer of insect-infecting viruses in aphids. Select mutations in the NRTD protein structurally predicted to bind aphid receptors are insecticidal to Myzus persicae and Aphis gossypii, the cotton aphid, when orally delivered via artificial diets. Together, the NRTD technology may serve as a biological control of poleroviruses and their aphid vectors.