Mechanisms of APOBEC3 Packaging into HIV-1

Apolipoprotein B mRNA editing enzyme catalytic polypeptide 3s (APOBEC3s, A3s) are single-stranded DNA cytidine deaminases with antiviral activity against diverse DNA and RNA viruses. The human APOBEC3 locus encodes seven members: A3A, A3B, A3C, A3D, A3F, A3G, and A3H. Of these, A3C, A3D, A3F, A3G, and A3H are packaged into HIV-1, lacking the viral infectivity factor (VIF, HIV-1Δ<i>vif</i>), while A3D, A3F, A3G, and A3H hap II exhibit strong antiviral activity. Packaging of A3s into virions is critical for viral restriction, yet the underlying mechanisms remain incompletely understood. A3 incorporation requires interactions with the GAG polyprotein, especially the matrix (MA) and nucleocapsid (NC) domains, and binding to cellular or viral RNAs. Specific amino acid residues within A3 proteins mediate these contacts, and A3G localization to lipid rafts facilitates packaging. While A3F and A3G incorporation have been extensively characterized, mechanisms for other A3s remain poorly defined. This review synthesizes current knowledge on A3 packaging, emphasizing the interplay of protein, RNA, and membrane determinants in efficient virion incorporation.