From subtraction libraries in the 80’s to microarrays in the 90’s and now next generation sequencing technologies, our understanding of the transcriptional response to virus infection has expanded significantly. However, these efforts still largely focus on only a limited number of cell types and are exclusively based on genes that demonstrate differential expression at a transcriptional level following IFN-I induction. Despite decades of IFN-I research, most of the efforts have focused on the antiviral effects of individual ISGs in either fibroblasts or antigen presenting cells. While this limited scope of study with regards to IFN-I was essential to discover and assemble the pathways involved in this response, it has largely ignored the fact that all differentiated cells can respond to IFN-I with little reason to believe this biology is uniform. Moreover, it is estimated that >95% of human pre-mRNAs are processed to yield multiple transcripts by alternative splicing, yet this concept has not been explored with respect to the IFN-I response. It is my hypothesis that differential gene expression of a common subset of ISGs is only a small fraction of the changes induced by IFN-I in a given cell type. Present work in my group aims to determine the cell-specific effects of human IFN-I stimulation on gene splicing by undertaking a hybrid sequencing approach, combining the benefits of both long- and short-read next-generation sequencing platforms. In an effort to determine whether these responses differ based on cell type and to identify genes that may show differential expression only at the level of a specific gene region, we have been performing isoform sequencing (Iso-Seq). This technique combines Illumina-based RNA-Seq, which provides quantitative data regarding transcript abundance with the Pacific Biosciences (PacBio) sequencing platform, which provides qualitative data identifying the composition of all full-length transcripts. This approach is being applied to a comprehensive panel of primary human cell types in response to IFN-I in an effort to generate an atlas of all ISGs as well as interferon-induced splice variants (ISVs).