HIV-1 Vif, APOBEC, and intrinsic immunity

Abstract

Members of the APOBEC family of cellular cytidine deaminases represent a recently identified group of proteins that provide immunity to infection by retroviruses and protect the cell from endogenous mobile retroelements. Yet, HIV-1 is largely immune to the intrinsic antiviral effects of APOBEC proteins because it encodes Vif (viral infectivity factor), an accessory protein that is critical for in vivo replication of HIV-1. In the absence of Vif, APOBEC proteins are encapsidated by budding virus particles and either cause extensive cytidine to uridine editing of negative sense single-stranded DNA during reverse transcription or restrict virus replication through deaminase-independent mechanisms. Thus, the primary function of Vif is to prevent encapsidation of APOBEC proteins into viral particles. This is in part accomplished by the ability of Vif to induce the ubiquitin-dependent degradation of some of the APOBEC proteins. However, Vif is also able to prevent encapsidation of APOBEC3G and APOBEC3F through degradation-independent mechanism(s). The goal of this review is to recapitulate current knowledge of the functional interaction of HIV-1 and its Vif protein with the APOBEC3 subfamily of proteins and to summarize our present understanding of the mechanism of APOBEC3-dependent retrovirus restriction.

Figure 1

Human APOBEC proteins. Members of the APOBEC family contain either one or two CDA domains. Proteins are aligned based on their catalytically active deaminase domain (CDA) depicted in green. Catalytically inactive CDA domains in two-domain enzymes are depicted in red. The consensus sequence for the CDA domains is shown at the bottom. Chromosomal association is shown on the left.

Figure 2

Sensitivity of viruses or retroelements to inhibition by cytidine deaminases. Viruses and retroelements are listed at the top and deaminases are listed on the left. Inhibition by deaminases was qualified as "no" (= insensitive to deaminase), weak (= weakly sensitive to deaminase), and "yes" (highly sensitive to deaminase). For HIV-1 and SIV viruses, the sensitivity to inhibition was further qualified as Vif-sensitive (red) and Vif-insensitive (blue). Sources of data are indicated in square brackets and include [11,31,39,42,43,73-76,79-81,84,86-88,98-106,126,143,144,175-187].

Figure 3

Model for Vif-induced degradation of APOBEC3G. (A) Sequence motifs in Vif implicated in the assembly of a Cul5-E3 ubiquitin ligase complex. Two conserved domains in Vif, the HCCH motif and the SLQ motif are involved in binding Cul5 and elongin C (EloC). Vif coordinates one zinc molecule, which may be required to stabilize a structure important for the binding of cullin 5 (Cul5). (B) Adaptor model for Vif-induced APOBEC3G degradation. According to this model Vif is an adaptor molecule with binding sites for APOBEC3G and the Cul5-E3 ligase complex (1). Expression of Vif results in the formation of an APOBEC3G-Vif-E3 ternary complex (2). This triggers poly-ubiquitination of APOBEC3G (3) resulting in the degradation of APOBEC3G (4).