Structural basis of antagonism of human APOBEC3F by HIV-1 Vif

Nat Struct Mol Biol. 2019 Dec;26(12):1176-1183. doi: 10.1038/s41594-019-0343-6. Epub 2019 Dec 2.

Abstract

HIV-1 virion infectivity factor (Vif) promotes degradation of the antiviral APOBEC3 (A3) proteins through the host ubiquitin-proteasome pathway to enable viral immune evasion. Disrupting Vif-A3 interactions to reinstate the A3-catalyzed suppression of human immunodeficiency virus type 1 (HIV-1) replication is a potential approach for antiviral therapeutics. However, the molecular mechanisms by which Vif recognizes A3 proteins remain elusive. Here we report a cryo-EM structure of the Vif-targeted C-terminal domain of human A3F in complex with HIV-1 Vif and the cellular cofactor core-binding factor beta (CBFβ) at 3.9-Å resolution. The structure shows that Vif and CBFβ form a platform to recruit A3F, revealing a direct A3F-recruiting role of CBFβ beyond Vif stabilization, and captures multiple independent A3F-Vif interfaces. Together with our biochemical and cellular studies, our structural findings establish the molecular determinants that are critical for Vif-mediated neutralization of A3F and provide a comprehensive framework of how HIV-1 Vif hijacks the host protein degradation machinery to counteract viral restriction by A3F.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Core Binding Factor beta Subunit / chemistry
  • Cryoelectron Microscopy
  • Cytosine Deaminase / antagonists & inhibitors
  • Cytosine Deaminase / chemistry*
  • Cytosine Deaminase / ultrastructure
  • HIV-1 / chemistry*
  • Humans
  • Immune Evasion
  • Models, Molecular
  • Protein Conformation
  • Protein Domains
  • Protein Interaction Mapping
  • Proteolysis
  • Structure-Activity Relationship
  • vif Gene Products, Human Immunodeficiency Virus / chemistry*
  • vif Gene Products, Human Immunodeficiency Virus / pharmacology
  • vif Gene Products, Human Immunodeficiency Virus / ultrastructure

Substances

  • Core Binding Factor beta Subunit
  • vif Gene Products, Human Immunodeficiency Virus
  • vif protein, Human immunodeficiency virus 1
  • APOBEC3F protein, human
  • Cytosine Deaminase