Loop 1 of APOBEC3C Regulates its Antiviral Activity against HIV-1

•Loop 1 residues in primate APOBEC3C and closely related A3s are under positive selection.•A3C in monkeys and apes replaced the highly active residues RK to WE during A3C gene evolution.•Replacing WE residues in loop 1 of A3C with RK turns A3C into a superior restriction factor.•Loop 1 residues RK caused enhancement of A3C catalytic activity by improved DNA interaction.•The cytosine deamination hotspots and cell-wide distribution of A3C were not affected by loop 1 residues RK.