Degradation-Independent Inhibition of APOBEC3G by the HIV-1 Vif Protein

Abstract

The ubiquitin–proteasome system plays an important role in the cell under normal physiological conditions but also during viral infections. Indeed, many auxiliary proteins from the (HIV-1) divert this system to its own advantage, notably to induce the degradation of cellular restriction factors. For instance, the HIV-1 viral infectivity factor (Vif) has been shown to specifically counteract several cellular deaminases belonging to the apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC3 or A3) family (A3A to A3H) by recruiting an E3-ubiquitin ligase complex and inducing their polyubiquitination and degradation through the proteasome. Although this pathway has been extensively characterized so far, Vif has also been shown to impede A3s through degradation-independent processes, but research on this matter remains limited. In this review, we describe our current knowledge regarding the degradation-independent inhibition of A3s, and A3G in particular, by the HIV-1 Vif protein, the molecular mechanisms involved, and highlight important properties of this small viral protein.

Special Issue “APOBECs and Virus Restriction”

“…To inhibit HIV, the APOBEC3 enzymes must become encapsidated into the budding virion [ 2 , 3 , 12 ]. This enables access to the viral genome and newly synthesized (-) DNA during reverse transcription.…”

“…HIV produces a protein called Vif which tries to prevent APOBEC3 encapsidation by multiple mechanisms. Stupfler et al describe how Vif uses multiple ways to block APOBEC3G activity [ 12 ]. Vif is a thermodynamically unstable protein since it is composed mainly of loops, without a stable core structure.…”

“…The main one is the co-transcription factor CBF-β. By CBF-β binding to Vif, it is relocalized to the cytoplasm, altering the transcription profile of the cell, which includes decreasing transcription of APOBEC3G [ 12 ]. Furthermore, Vif can bind to the 5′UTR of A3G mRNA and impair translation by 70–75%.…”

“…Furthermore, Vif can bind to the 5′UTR of A3G mRNA and impair translation by 70–75%. Stupfler et al discuss how two stem-loops, SL2–SL3, in the 5′UTR are specifically bound by Vif and cause ribosome stalling [ 12 ]. Vif can also inhibit packaging of APOBEC3G through a physical interaction.…”

“…Finally, the most well-known method is through Vif mediating the degradation of APOBEC3 enzymes through ubiquitination and proteasomal degradation. Vif acts as the substrate receptor in a Cullin5 ubiquitin ligase complex [ 12 ]. Nonetheless, some APOBEC3G can still escape.…”