The hallmark of APOBEC3G-dependent retrovirus restriction is plus-strand G-to-A hypermutation, which is caused by the deamination of minus-strand cDNA C-to-U during reverse transcription [17, 18, 20, 24, 25] . The deamination of cytosines within singlestrand DNA requires glutamate 259 (E259) of APOBEC3G [47] [48] [49] . Based on homology to structurally defined deaminases, E259 likely functions by helping position the water molecule that ultimately initiates the deamination reaction by attacking the cytosine ring (as a hydroxide; reviewed by [17, 23, 50, 51] ).