Defining the genomic and ecological landscapes of the human anellome

Human anelloviruses (ANVs) represent one of the most diverse, prevalent, and persistent viral communities within the human virome and constitute dominant members of the commensal viral ecosystem. Despite their ubiquity and emerging associations with immune modulation and hematologic malignancy, the genomic diversity and community organization of the human ANV virome (anellome) remain incompletely resolved. This limitation is driven in part by fragmented reference datasets, inconsistent taxonomic annotation, and geographic underrepresentation, particularly for Asian populations. A geographically expanded reference and standardized analytical framework are therefore needed to profile the human anellome at species-level and lineage-level resolution. We integrated metagenomic sequencing data from 6348 Chinese samples with globally available ANV genomes to construct an expanded phylogenomic resource for the human anellome. This integration improved Asian representation and expanded represented human ANV diversity to 771 species-level taxa, comprising 91 ICTV-recognized human-associated species and 680 provisional new species (PNS), corresponding to an approximately eightfold expansion in represented species-level diversity. The resulting framework enabled high-resolution profiling of personal anellomes. The richest individual profile contained 305 species-level taxa and 2071 lineages, indicating extensive intra-host ANV diversity under the expanded reference framework. Across analyzed cohorts and public metadata, we identified recurrent core anellome components characterized by high detection frequency, abundance, geographic representation, cross-cohort reproducibility, and longitudinal persistence. Several core lineages showed significant inverse associations with CD4 T-cell counts in HIV-infected individuals. Paired peripheral blood mononuclear cell (PBMC) and plasma analyses further identified compartment-associated differences in diversity, composition, and lineage enrichment. Within this framework, a TTMV::RARA -associated Betatorquevirus clade showed higher ORF2 conservation, RUNX1 motif enrichment, and PBMC-biased distribution compared with background clades. These findings support the human anellome as a structured commensal viral community that can be resolved at species-level and lineage-level resolution. The HANVdb Resource provides a reusable framework for investigating ANV diversity, anellome ecology, immune-associated variation, compartmental organization, and lineage-level hypotheses relevant to viral integration-associated disease.