(1) Vif facilitates the degradation of the antiviral proteins A3G and A3F by hijacking the cellular ubiquitin-proteasome pathway. Vif connects the cellular E3 ubiquitin ligase with A3G/A3F, which initiates the polyubiquitination of the A3 proteins, followed by their degradation by the 26S proteasome. (2) Vif also impairs the translation of A3 mRNA and therefore reduces the cellular protein pool. (3) Finally, Vif may also interfere with the encapsidation of A3 proteins into the budding virus in the absence of A3G/F degradation. Adapted, with permission, from Chiu et al. 2008.

In cells infected with ΔVif HIV-1, A3G is not degraded and is effectively incorporated into the budding virus and transferred to the next target cell, where it exerts antiviral effects at multiple levels. (1) A3G can inhibit the elongation of the reverse transcriptase in a deaminase-independent manner. Presumably, A3G binds directly to the viral RNA and thereby impairs the movement of the reverse transcriptase along the RNA template. (2) Most importantly, A3G can trigger massive deamination of dC to dU during synthesis of the viral minus strand. During synthesis of the DNA plus strand, adenosines are incorporated instead of the original guanines, resulting in G-to-A mutation. (3) Finally, A3G also inhibits viral DNA integration and provirus formation, probably by inducing defects in tRNA cleavage during plus-strand DNA transfer, leading to the formation of aberrant viral DNA ends. A3G also interacts with the integrase enzyme of HIV-1, which might interfere with the integrity of the integration complex, resulting in diminished integration rates. Figure was adapted from Chiu et al. 2008 with permission.

(A) Schematic structure of the Vif domains. The N-terminal A3G binding sites are indicated in orange, A3F binding sites in blue. The structure of the H¹⁰⁸x₅Cx_17-18Cx_3-5H¹³⁹ zinc finger motif that connects Vif to cullin5 is shown in gray as well as the viral BC-box (S¹⁴⁴LQYLA¹⁴⁹) that facilitates the binding to elongin C (EloC). Vif multimerization is facilitated by the hydrophobic amino acids P¹⁶¹PLP¹⁶⁴ (purple). At the C-terminus the Gag, NC, and membrane binding domain is located (indicated in violet). B) Vif initiates the degradation of A3G by binding to the cytidine deaminase and simultaneously to an E3 ubiquitin ligase complex. This complex consists of cullin5 (Cul5), elonginB (EloB), elonginC (EloC), and a ring finger protein (Rbx). Rbx binds to an unknown E2 ubiquitin-conjugating enzyme (E2). Therefore Vif connects the ligase complex and its A3 protein substrates to initiate polyubiquitination and proteasome-mediated degradation of A3 proteins.