Host control and regulation of human anellovirus persistence

Abstract

Anelloviruses are the most abundant and diverse eukaryotic viruses known to infect humans and can persist throughout our lifetimes. Despite their ubiquity, the host factors governing their physiologic distribution and abundance remain poorly understood. Here, we construct a viral pangenome of 2,023 strains to quantify anellovirus DNA in >1.1 million participants spanning three genetic biobanks. Genome-wide association studies identify 121 loci linked to viral persistence, predominantly via immune regulation by NF-kB signaling. Further, we associate variable anellovirus detection with conditions characterized by immune dysfunction, including lymphoid malignancies. By screening 3.2 petabases of human single-cell sequencing data, we identify myeloid progenitors in the bone marrow as a prominent site of anellovirus transcription in vivo. Finally, Perturb-seq of anellovirus proteins reveals that anellovirus ORF2, particularly from Alphatorquevirus, attenuates TNF-a-induced NF-kB signaling, connecting host genetic variation, cellular context, and viral immunomodulation to characterize the persistence of the eukaryotic human virome's most abundant component.

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BibTeX RIS

BibTeX

@misc{gutierrez2026host,
  title = {{Host control and regulation of human anellovirus persistence}},
  author = {J. C. Gutierrez and T. A. Ali and C. C. Honeycutt and J. H. Neo and K. Helmsauer and S. S. Nyeo and A. Le and A. J. Vela and L. C. Kida and A. A. Varela and R. C. Ardy and E. Metzner and J. C. Ulirsch and R. S. Dhindsa and P. P. Fiziev and R. Chikhi and T. M. Norman and K. K. Dey and C. A. Lareau},
  howpublished = {bioRxiv},
  year = {2026},
  month = nov,
  doi = {10.64898/2026.11.05.764726},
  url = {https://www.biorxiv.org/content/10.64898/2026.11.05.764726v1},
  note = {CC BY},
}

RIS

TY  - UNPB
TI  - Host control and regulation of human anellovirus persistence
AU  - J. C. Gutierrez
AU  - T. A. Ali
AU  - C. C. Honeycutt
AU  - J. H. Neo
AU  - K. Helmsauer
AU  - S. S. Nyeo
AU  - A. Le
AU  - A. J. Vela
AU  - L. C. Kida
AU  - A. A. Varela
AU  - R. C. Ardy
AU  - E. Metzner
AU  - J. C. Ulirsch
AU  - R. S. Dhindsa
AU  - P. P. Fiziev
AU  - R. Chikhi
AU  - T. M. Norman
AU  - K. K. Dey
AU  - C. A. Lareau
PY  - 2026
DA  - 2026/11/05
PB  - bioRxiv
DO  - 10.64898/2026.11.05.764726
UR  - https://www.biorxiv.org/content/10.64898/2026.11.05.764726v1
AB  - Anelloviruses are the most abundant and diverse eukaryotic viruses known to infect humans and can persist throughout our lifetimes. Despite their ubiquity, the host factors governing their physiologic distribution and abundance remain poorly understood. Here, we construct a viral pangenome of 2,023 strains to quantify anellovirus DNA in >1.1 million participants spanning three genetic biobanks. Genome-wide association studies identify 121 loci linked to viral persistence, predominantly via immune regulation by NF-kB signaling. Further, we associate variable anellovirus detection with conditions characterized by immune dysfunction, including lymphoid malignancies. By screening 3.2 petabases of human single-cell sequencing data, we identify myeloid progenitors in the bone marrow as a prominent site of anellovirus transcription in vivo. Finally, Perturb-seq of anellovirus proteins reveals that anellovirus ORF2, particularly from Alphatorquevirus, attenuates TNF-a-induced NF-kB signaling, connecting host genetic variation, cellular context, and viral immunomodulation to characterize the persistence of the eukaryotic human virome's most abundant component.
ER  -

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