Human immunodeficiency virus type 1 Virion infectivity factor (Vif)–Apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3G (APOBEC3G) protein–protein interface (HIV-1 Vif–APOBEC3G PPI)

The HIV-1 Vif-APOBEC3G protein-protein interface is a critical regulatory site where the viral Virion infectivity factor (Vif) interacts with the host's innate antiviral enzyme, Apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3G (APOBEC3G) (Harris & Liddament, 2004, Nature Reviews Immunology). In the absence of Vif, APOBEC3G is packaged into budding HIV-1 virions and subsequently induces extensive G-to-A hypermutations in the viral genome during reverse transcription, rendering the virus non-infectious (Sheehy et al., 2002, Nature). To counteract this, HIV-1 Vif binds to APOBEC3G and recruits a Cullin 5-based E3 ubiquitin ligase complex (including Elongin B/C and CBF-beta) to trigger the polyubiquitination and subsequent proteasomal degradation of the host protein (Guo et al., 2014, Nature). Targeting this interface with small molecules aims to disrupt the Vif-APOBEC3G binding, thereby stabilizing APOBEC3G and allowing it to exert its natural restriction activity against the virus (Cen et al., 2010, Chem Biol). This approach represents a novel therapeutic strategy to enhance the host's innate immune response and overcome viral evasion mechanisms. While several experimental inhibitors like RN-18 and IMB-26 have demonstrated proof-of-concept, no drugs targeting this interface are currently FDA-approved (Matsui et al., 2014, Journal of Virology). Therapeutic challenges include the flat, expansive nature of the protein-protein interface and the need for high specificity to avoid affecting other host APOBEC proteins (Wells & McClendon, 2007, Nature).

Other names

Vif-APOBEC3G interactionVif-A3G complexHIV-1 Vif-A3G interfaceVif-APOBEC3G PPI

Inhibition of the physical interaction between the HIV-1 Vif protein and the host APOBEC3G protein, preventing the recruitment of the Cullin 5 E3 ubiquitin ligase complex and subsequent proteasomal degradation of APOBEC3G (Cen et al., 2010, Chem Biol; Nathans et al., 2008, PNAS).