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.