Towards Inhibition of Vif-APOBEC3G Interaction: Which Protein to Target?

Abstract

APOBEC proteins appeared in the cellular battle against HIV-1 as part of intrinsic cellular immunity. The antiretroviral activity of some of these proteins is overtaken by the action of HIV-1 Viral Infectivity Factor (Vif) protein. Since the discovery of APOBEC3G (A3G) as an antiviral factor, many advances have been made to understand its mechanism of action in the cell and how Vif acts in order to counteract its activity. The mainstream concept is that Vif overcomes the innate antiviral activity of A3G by direct protein binding and promoting its degradation via the cellular ubiquitin/proteasomal pathway. Vif may also inhibit A3G through mechanisms independent of proteasomal degradation. Binding of Vif to A3G is essential for its degradation since disruption of this interaction is predicted to stimulate intracellular antiviral immunity. In this paper we will discuss the different binding partners between both proteins as one of the major challenges for the development of new antiviral drugs.

Figure 1

Schematic representation of Vif and A3G domains involved in the interaction of both proteins. (a) Vif binds A3G through specific residues located in the N-terminal region. Amino acids in Vif that are involved in the interaction with A3G are shown in pink. C-terminal Vif domains involved in targeting A3G for proteasomal degradation are shown in orange (zinc binding HCCH domain), and light blue (SLQXLA). The multimerization domain is purple. (b) The catalytic domains (CD1 and CD2) and Vif-binding regions of A3G protein are represented. Amino acids 126–132 are involved in A3G encapsidation and interaction with Vif and are represented in green and red.