Incorporation of Mouse APOBEC3 into Murine Leukemia Virus Virions Decreases the Activity and Fidelity of Reverse Transcriptase

APOBEC3 proteins are restriction factors that induce G¡A hypermutation in retroviruses during replication as a result of cyt-idine deamination of minus-strand DNA transcripts. However, the mechanism of APOBEC inhibition of murine leukemia vi-ruses (MuLVs) does not appear to be G¡A hypermutation and is unclear. In this report, the incorporation of mA3 in virions resulted in a loss in virion reverse transcriptase (RT) activity and RT fidelity that correlated with the loss of virion-specific infectivity. APOBEC3G (hA3G) in humans and APOBEC3 (mA3) in miceare cytidine deaminases that act on single-stranded DNA dur-ing reverse transcription, resulting in G¡A hypermutation of newly synthesized proviral DNA (1, 2). Although exogenous mu-rine leukemia viruses (MuLVs) are relatively insensitive to the actions of mA3 (2–7), several studies have reported partial inhibi-tion of exogenous MuLVs after incorporation of mA3 (2, 3, 6, 8–11). Furthermore, the finding that Rfv3, a resistance gene for Friend erythroleukemia, encodes mA3 and is responsible for a decreased infectious titer of the Friend MuLV (Fr-MuLV) (11–13) strongly suggests that mA3 inhibits the replication of exogenou