Suppression of HBV replication by LAM/siRNA promotes host genome deamination by A3A and A3B.
Lucifora et al .17 and Qiao et al .55 demonstrated that A3A, A3B, and AID can edit cccDNA but do not affect the host genome in HBV-infected cells due to association with HBc protein. Faure-Dupuy et al . did not detect A3B deamination of the host genome by NGS analysis as well30. However, our recent study observed a trend towards APOBEC/AID-mediated deamination of the host genome in cells with lower rates of HBV replication31, suggesting that the use of APOBEC/AID therapeutic strategies may be disadvantageous in patients receiving antivirals or in patients with low viral loads.
Thus, we assessed potential impact of LAM and siRNA treatments on off-site genomic deamination of genes implicated in numerous types of human cancers (TP53 , AIRD2 , andPAX5 )56 by A3A, A3B, and AID. To study the impact of LAM/siRNA, a model of very active rcccDNA-driven HBV replication, which does appear susceptible to APOBEC/AID-driven mutations, was used31. Indeed, CRISPRa of A3A, A3B, and AID did not lead to deamination in any of the studied genes (Figure 5). On the other hand, LAM treatment resulted in deamination ofTP53 by A3A. Prolific deamination of TP53 by A3A and A3B was also detected upon siRNA treatment (Figure 5A). Under these experimental conditions, no mutations were found in ARID2 andPAX5 genes (Figure 5B, C).
Together, these results indicate that therapeutic suppression of HBV replication makes the host genome prone to A3A and A3B pro-mutagenic activity.