APOBEC3DE Antagonizes Hepatitis B Virus Restriction Factors APOBEC3F and APOBEC3G.

The APOBEC3 locus consists of seven genes (A3A-A3C, A3DE, A3F-A3H) that encode DNA cytidine deaminases. These enzymes deaminate single-stranded DNA, the result being DNA peppered with CG →TA mutations preferentially in the context of 5'TpC with the exception of APOBEC3G (A3G), which prefers 5'CpC dinucleotides. Hepatitis B virus (HBV) DNA is vulnerable to genetic editing by APOBEC3 cytidine deaminases, A3G being a major restriction factor. APOBEC3DE (A3DE) stands out in that it is catalytically inactive due to a fixed Tyr320Cys substitution in the C-terminal domain. As A3DE is closely related to A3F and A3G, which can form homo- and heterodimers and multimers, the impact of A3DE on HBV replication via modulation of other APOBEC3 restriction factors was investigated. A3DE binds to itself, A3F, and A3G and antagonizes A3F and, to a lesser extent, A3G restriction of HBV replication. A3DE suppresses A3F and A3G from HBV particles, leading to enhanced HBV replication. Ironically, while being part of a cluster of innate restriction factors, the A3DE phenotype is proviral. As the gorilla genome encodes the same Tyr320Cys substitution, this proviral phenotype seems to have been selected for.