Anelloviruses are the principal constituent of the commensal human virome. However, their structure and features were not well studied and remain elusive.
Here, researchers from Ring Therapeutics use cryo-EM to solve the first high-resolution structure for Anellovirus generated in insect and mammalian cells, which could not only help understand their interactions with the immune system but also provide a viral vector platform for gene therapy development
This paper reports the first cryogenic electron microscopy (cryo-EM) structure of an anellovirus-like particle, which provides important new insights into the biology and immune evasion mechanisms of these ubiquitous human viruses. Anelloviruses, which comprise a major portion of the human virome, are characterized by their ability to evade the immune system and establish persistent infections despite being widespread in the human population.
The cryo-EM structures reveal that the anellovirus capsid is composed of 60 jelly roll domain-containing capsid proteins assembled into an icosahedral core. Extending out from this core are spike domains that form a crown-like structure around the 5-fold symmetry axis of the particle. These spike domains consist of two subdomains - a relatively conserved P1 subdomain at the base, and a highly variable P2 subdomain at the apex that contains the hypervariable region (HVR) of the capsid protein.
The authors propose that this structural organization, with the variable P2 subdomain exposed on the exterior of the particle while the more conserved P1 subdomain is buried, represents an immune evasion strategy employed by anelloviruses. By displaying the HVR epitopes as immunological decoys, anelloviruses may be able to hide vulnerable conserved regions from antibody neutralization. This would help explain the weak immune responses and ability of these viruses to establish persistent, multi-strain infections in humans.
The similarity of the anellovirus jelly roll core structure to that of circoviruses suggests an evolutionary relationship, but the anellovirus-specific spike domain and C-terminal regions represent novel structural features. The basic, positively-charged residues lining the interior of the jelly roll core are proposed to facilitate binding and packaging of the viral genome. Overall, this work provides the first experimental evidence for the capsid protein identity and structural organization of anelloviruses, shedding light on how these enigmatic viruses have evolved sophisticated mechanisms to evade host immunity.
Liou, Sh., Boggavarapu, R., Cohen, N.R. et al. Structure of anellovirus-like particles reveal a mechanism for immune evasion. Nat Commun15, 7219 (2024). https://doi.org/10.1038/s41467-024-51064-8
