Vanderbilt-coordinated human Virome Collaborative Center (V2C2) - Viruses are responsible for significant morbidity/mortality at the heart of most of global pandemics of the 21st century. Recent developments in technical and bioinformatic capabilities to address viral sequence diversity in a high-throughput context alongside integrated host responses have ushered in the potential for investigating viral presence and consequences at epidemiologic scale. Here, we establish the Vanderbilt-coordinated Virus Characterization Center (V2C2) to respond to RFA-RM-23-019 to address the central call of the Human Virome Program (HVP)—to provide a comprehensive, annotated, host-contextualized virome. The central theme/hypothesis of V2C2 is that unrecognized eukaryotic/prokaryotic viruses in human ecology (1) exhibit important interactions with host biology and flora, with prevalence of viral persistence or integration related to variation in biologically relevant phenotypes in healthy individuals (e.g., obesity, inflammation). To address this hypothesis, we will study (1) ≈2250 Hispanic/Latinx individuals at the US-Mexico border (ages 8-90; 1750 with 2 serial samples already collected with up to ≈20 years follow-up; 500 with 3 serial samples to be prospectively collected over ≈4 years); (2) ≈200 children (ages 0-5, CANOE-VU) with serial samples (some already collected). We propose a broad sampling scheme for prospective samples, spanning ocular, nasal, oropharyngeal, plasma, blood (extracellular vesicles, PBMCs, platelets), urine, and stool samples, and accompanying placental and breast milk samples (pediatric cohort), and will prioritize plasma (all samples) and 3 additional sample types (prospective only) based on consortium discussion. Our host-contextualized viral characterization approach (Aim 1) will include viral whole metagenomic/metatranscriptomic sequencing (to assess viral presence, function) with targeted capture-based confirmation. With other HVP members (e.g., Functional Interaction awardees), we will study host-viral interactions (Aim 2) via (1) host genomics (for integration); (2) viral tropism studies (using single cell and in vitro infection studies); (3) host response characterization (at the cellular and organism-wide level with proteomics/transcriptomics). In Aim 3, we will establish a repository of harmonized metadata and molecular information for data sharing in an ethically responsible manner to allow multi-omic connections between longitudinal phenotypes and host-viral characteristics. We will execute this vision collaboratively within the HVP via (1) a core structure (led by administrative) that addresses biospecimen collection, assay, data analysis/submission, and ethical/legal/social implications that (2) follow a pre-determined series of milestones (predicated on establishing consortium-wide protocols in the initial 6 month planning phase). V2C2 leadership has (1) published expertise in large sample viral characterization/biological discovery, with extensive preliminary data bearing directly on HVP; (2) cohort epidemiology; (3) extensive consortium experience in NIH, CDC, and Common Fund initiatives. The effectiveness of V2C2 is augmented by strong community engagement (CCHC), institutional support, and program management staff with experience at the scale of HVP.
