TY - JOUR
T1 - Control of Human Anelloviruses by Cytosine to Uracil Genome Editing
AU - Timmerman, Anne L
AU - Kaczorowska, Joanna
AU - Deijs, Martin
AU - Bakker, Margreet
AU - van der Hoek, Lia
N1 - Funding Information: J.K., A.L.T., M.D., and L.v.d.H., study design. M.B. investigation and resources. A.L.T., J.K., and M.D., C to T genome editing bioinformatics. A.L.T., wet lab experiments and figures. A.L.T. and L.v.d.H., writing of the manuscript with contributions from all authors. All authors approved the submitted version of the manuscript. This research was funded by the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie Actions grant agreement no. 721367 (HONOURs). Funding Information: We thank all participants and coworkers of the Amsterdam Cohort Studies (ACS) on HIV infection and AIDS, a collaboration between the Public Health Service of Amsterdam, the Amsterdam University Medical Center of the University of Amsterdam, the Jan van Goyen Medical Center, and the HIV Focus Center of the DC Clinics. Funding was supported by Netherlands HIV Monitoring Foundation and financially and the Center for Infectious Disease Control of the Netherlands National Institute for Public Health and the Environment. Publisher Copyright: Copyright © 2022 Timmerman et al.
PY - 2022/11
Y1 - 2022/11
N2 - Anelloviruses are the most common viruses infecting humans. Every human carries a nonpathogenic personal anellovirus virome (anellome), yet it is unknown which mechanisms contribute to its stability. Here, we assessed the dynamics and impact of a host antiviral defense mechanism - cytidine deaminase activity leading to C to U editing in anelloviruses - on the stability of the anellome. We investigated anellome sequence data obtained from serum samples collected every 6 months from two healthy subjects followed for more than 30 years. The subjects were infected by a total of 64 anellovirus lineages. Minus-stranded C to U editing was observed in lineages belonging to the Alpha-, Beta-, and Gammatorquevirus genera. The edited genomes were present within virus particles, therefore editing must have occurred at the late stages of the virus life cycle. Editing was favored by 59-TC contexts in the virus genome, indicating that apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like, catalytic subunit 3 or A3 (APOBEC3) proteins are involved. Within a lineage, mutational dynamics varied over time and few fixations of mutations were detected, indicating that C to U editing is a dead end for a virus genome. We detected an editing coldspot in the GC-rich regions, suggesting that the GC-rich region is crucial for genome packaging, since only packaged virus particles were included in the analysis. Finally, we noticed a lineage-specific reduced concentration after an editing event, yet no clearance. In conclusion, cytidine deaminase activity does not clear anelloviruses, nor does it play a major role in virus evolution, but it does contribute to the stability of the anellome. IMPORTANCE 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.
AB - Anelloviruses are the most common viruses infecting humans. Every human carries a nonpathogenic personal anellovirus virome (anellome), yet it is unknown which mechanisms contribute to its stability. Here, we assessed the dynamics and impact of a host antiviral defense mechanism - cytidine deaminase activity leading to C to U editing in anelloviruses - on the stability of the anellome. We investigated anellome sequence data obtained from serum samples collected every 6 months from two healthy subjects followed for more than 30 years. The subjects were infected by a total of 64 anellovirus lineages. Minus-stranded C to U editing was observed in lineages belonging to the Alpha-, Beta-, and Gammatorquevirus genera. The edited genomes were present within virus particles, therefore editing must have occurred at the late stages of the virus life cycle. Editing was favored by 59-TC contexts in the virus genome, indicating that apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like, catalytic subunit 3 or A3 (APOBEC3) proteins are involved. Within a lineage, mutational dynamics varied over time and few fixations of mutations were detected, indicating that C to U editing is a dead end for a virus genome. We detected an editing coldspot in the GC-rich regions, suggesting that the GC-rich region is crucial for genome packaging, since only packaged virus particles were included in the analysis. Finally, we noticed a lineage-specific reduced concentration after an editing event, yet no clearance. In conclusion, cytidine deaminase activity does not clear anelloviruses, nor does it play a major role in virus evolution, but it does contribute to the stability of the anellome. IMPORTANCE 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.
KW - APOBEC3
KW - C to U genome editing
KW - anellome
KW - anellovirus
KW - torque teno midi virus
KW - torque teno mini virus
KW - torque teno virus
KW - virome
UR - http://www.scopus.com/inward/record.url?scp=85144595182&partnerID=8YFLogxK
U2 - https://doi.org/10.1128/msphere.00506-22
DO - https://doi.org/10.1128/msphere.00506-22
M3 - Article
C2 - 36374042
VL - 7
SP - e0050622
JO - mSphere
JF - mSphere
SN - 2379-5042
IS - 6
ER -