Modified Project Summary/Abstract Section The RUSTBELT CFAR Systems Biology & Biostatistics Core F supports a wide range of CFAR investigators by providing new multi-omic technologies, advanced biostatistics, and computational analysis of big data. It also offers a stronger foundation in functional immunology studies and a comprehensive ‘omic data management and training platform. The primary mission of Core F is to deliver systems biology approaches that enable integration of various layers of host immune responses, from molecular triggers to transcriptional signatures and interactions with resident microbiota. We will continue to support functional immunology studies that are fundamental to HIV research. The Core helps investigators improve research rigor and reproducibility by implementing best practices for study design, analysis, and public sharing of results. In Aim 1, Core F will support genomics and microbiome research in HIV immunology and pathogenesis by providing a robust platform for transcriptional analysis via RNA-seq and deep sequencing in clinical and animal models of HIV infection. In Aim 2, Core F offers training and consultation in functional immunology, along with centralized access to cutting-edge immunologic technologies, protocols, and training for isolating, manipulating, culturing, and expanding primary immune cells from blood and tissue. This supports the RUSTBELT CFAR’s objectives in HIV transmission, sex research, cure, and pathogenesis translation. In Aim 3, Core F facilitates all aspects of systems biology studies by offering centralized data acquisition, management, and reporting for all cohorts and ‘omics datasets. It uses high-capacity assay and analysis workflows and publicly available ‘omic data to build publications and databases. Lastly, in Aim 4, this service includes the collection and preparation of ‘omic and functional data for distribution to investigators, gathering associated de-identified patient annotations needed for analysis and study publication. Core F performs biostatistical correlation analysis to identify key drivers of protective immune responses, assists in designing validation strategies and manuscript preparation, and provides metadata and data standardization pipelines for uploading results to public databases. By offering foundational immune modeling support paired with multi-omic methodologies to identify key drivers or biomarkers of the host-virus interface in HIV, Core F fosters a comprehensive systems biology approach that is essential to supporting CFAR investigators in their translational research on HIV cure, prevention, response to treatment, and immunopathology.