Lettuce necrotic yellows virus (LNYV) is endemic to Australia and New Zealand, with populations in both countries made up of two subgroups (SI and SII). Phylogenetic analyses have indicated that SII emerged more recently and has dispersed more rapidly than SI, to the point where SI appears to have become extinct in Australia. While symptoms don’t differentiate infection by these subgroups, we hypothesise that SII impacts the host at the molecular level to favour its dispersal. We have used RT-qPCR, metabolome, and transcriptome analyses to identify molecular pathways of interest at 28 dpi of the host plant Nicotiana glutinosa. Initial data indicate common responses to infection by the LNYV subgroups as well as subgroup specific responses, supporting our hypothesis. RT-qPCR data showed differences in mRNA accumulation of several genes, such as AOX1a and WRKY70, in response to each subgroup. Specific metabolites have been identified through analysis of sugar, amino acid, organic acid, and fatty acid profiling that also indicate different responses to infection by each LNYV subgroup. Transcriptome profiling supports these data as well as highlighting other subgroup specific gene expression responses – 82 genes were shown to be upregulated and 114 downregulated in response to SII compared to SI. These combined data show LNYV-SII influences host responses, such as amino acid and energy production, to promote infection and, thus, dispersal. The complexities of the pathways involved are currently being analysed, and aspects will be presented. Findings of this study will make important contributions to our understanding of the complicated mechanisms of plant responses to virus infection and virus spread, particularly by a cytorhabdovirus.