APOBECs and virus restriction

Abstract

The APOBEC family of single-stranded DNA cytosine deaminases comprises a formidable arm of the vertebrate innate immune system. Pre-vertebrates express a single APOBEC, whereas some mammals produce as many as 11 enzymes. The APOBEC3 subfamily displays both copy number variation and polymorphisms, consistent with ongoing pathogenic pressures. These enzymes restrict the replication of many DNA-based parasites, such as exogenous viruses and endogenous transposable elements. APOBEC1 and activation-induced cytosine deaminase (AID) have specialized functions in RNA editing and antibody gene diversification, respectively, whereas APOBEC2 and APOBEC4 appear to have different functions. Nevertheless, the APOBEC family protects against both periodic viral zoonoses as well as exogenous and endogenous parasite replication. This review highlights viral pathogens that are restricted by APOBEC enzymes, but manage to escape through unique mechanisms. The sensitivity of viruses that lack counterdefense measures highlights the need to develop APOBEC-enabling small molecules as a new class of anti-viral drugs.

Keywords: APOBEC family; Cytosine deaminases; DNA viruses; Innate immunity; Retroviruses.

Figure 1. APOBEC hallmarks

(A) A schematic of the single-stranded DNA cytosine deamination reaction catalyzed by APOBEC family members. (B) A ribbon model of the A3G catalytic domain showing its globular structure and a blow-up of the zinc-coordinating active site (cysteines are depicted in yellow, histidine in blue, and the catalytic glutamate in red). (C) Schematics of the A3 gene composition of several current mammals depicted above the repertoire of a likely common ancestor and current non-mammalian vertebrates. The color scheme distinguishes phylogenetic subfamilies. See the text for additional details.

Figure 2. Model for HIV-1 restriction by APOBEC3 enzymes and virus protection by Vif

HIV-1 infection of T cells allows expression of Vif, which recruits CBF-β to form an E3 ubiquitin ligase complex that degrades several different A3 proteins (A3D, A3G, A3F, and A3H). In the absence of Vif, these A3 proteins can package into virions. During subsequent infection of susceptible cells, these A3 proteins deaminate viral cDNA cytosines to uracils and directly impede reverse transcription. Viral cDNA uracils template the insertion of genomic strand adenines and result in hallmark G-to-A hypermutations. See the text for details [adapted from (Harris et al., 2012), based upon prior studies].

Figure 3

Model for glyco-Gag protection from restriction by murine A3. The left image depicts glyco-Gag as an oblong blue shape that prevents A3 from accessing reverse transcription complexes. Capsids are primarily composed of the classical Gag (circles not depicted on the left panel). The right panel depicts Gag as a blue oval that causes the capsid to be more loosely formed and susceptible to the A3-mediated block in reverse transcription. Although low levels of G-to-A mutation have been reported, these changes are a minor outcome of A3 activity and are not depicted for clarity. See the text for additional details.