Control of Human Anelloviruses by Cytosine to Uracil Genome Editing

Abstract

Despite significant attention on anellovirus research, the interaction between the anellovirus virome and the human host remains unknown. We show the dynamics of APOBEC3-mediated cytidine deaminase activity on anelloviruses during a 30-year period of chronic infection and postulate that this antiviral mechanism controls anelloviruses. These results expand our knowledge of anellovirus-host interactions, which may be important for the design of gene therapies.

Anelloviruses versus human immunity: how do we control these viruses?

“…We suggest that in future research, anelloviruses should not be approached as one virus, but several. Differences between subgenera and/or isolates were detected regarding increased anellovirus load in immunosuppressed individuals (Blatter et al 2018 ), APOBEC3 susceptibility (Timmerman et al 2022 ) and antibody reactivity (Venkataraman et al 2022 ). It would be of interest to investigate whether subgenera, or isolates, are more immunogenic or tolerogenic compared to others.…”

“…These predictions were recently confirmed by us. By next generation sequencing, we investigated hypermutations in 64 anellovirus isolates in healthy people, and revealed that all three human anellovirus genera are affected by C to U deamination, with some isolates more vulnerable to deamination than others (Timmerman et al 2022 ). The U-containing genomes were packaged inside intact virus particles, which we know because the clinical materials were treated with DNAse prior to analysis.…”

“…The fact that uracils were found in the genomes within intact virus particles suggests that editing must have occurred at the late stage of the replication cycle, since the mRNA encoding an intact viral capsid could not have been transcribed from edited DNA. According to the observed nucleotide context, we considered A3C, A3D, A3F, and A3H as potential candidates acting on the negative sense anellovirus genome (Timmerman et al 2022 ). Of note, APOBEC3 activity did not seem to change an anellome, as isolates that were most affected by editing were rarely lost in their hosts during the > 30 years that we were able to follow chronic anellovirus infections in individuals.…”

Human Anelloviruses: Influence of Demographic Factors, Recombination, and Worldwide Diversity

“…Since anelloviruses use a host polymerase ( 35 ), they might not exhibit high mutation rates ( 10 ), although some indirect evidence casts doubt on this assumption. On one hand, anellovirus genomes with hypermutation patterns consistent with antiviral host innate immunity exerted by APOBEC3 proteins have been described ( 36 ). However, it has been suggested that this antiviral defense mechanism does not play a major role in viral evolution but contributes to the stability of the anellome ( 36 ).…”

“…On one hand, anellovirus genomes with hypermutation patterns consistent with antiviral host innate immunity exerted by APOBEC3 proteins have been described ( 36 ). However, it has been suggested that this antiviral defense mechanism does not play a major role in viral evolution but contributes to the stability of the anellome ( 36 ). On the other hand, the ORF1 of anelloviruses has conserved motifs similar to Rep protein motifs, present in the Circoviridae and Geminiviridae families.…”