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The Apoliprotein B mRNA-editing, enzyme-catalytic, polypeptide-like (APOBEC) 3 is a multi-isoform member of the cytidine deaminase family of enzymes that act on monomeric nucleoside and nucleotide substrates. Similar to TRIM5alpha which targets incoming retroviral capsids, APOBEC3 plays a major role in cellular defense against retroviral infection as at least two isoforms, APOBEC3G and to a lesser extent APOBEC3F, can be incorporated HIV-1 virions and induce hypermutation in the newly synthesized viral DNA and thus destabilize the viral genome. This innate mechanism of retroviral resistance is counteracted by the HIV-1 Vif protein by inducing the ubiquitization and degradation of APOBEC3G; a single amino acid substitution (D128K) blocks APOBEC3G depletion without affecting its inhibitory activity.