APOBEC proteins and intrinsic resistance to HIV-1 infection

Abstract

Members of the APOBEC family of cellular polynucleotide cytidine deaminases, most notably APOBEC3G and APOBEC3F, are potent inhibitors of HIV-1 infection. Wild type HIV-1 infections are largely spared from APOBEC3G/F function through the action of the essential viral protein, Vif. In the absence of Vif, APOBEC3G/F are encapsidated by budding virus particles leading to excessive cytidine (C) to uridine (U) editing of negative sense reverse transcripts in newly infected cells. This registers as guanosine (G) to adenosine (A) hypermutations in plus-stranded cDNA. In addition to this profoundly debilitating effect on genetic integrity, APOBEC3G/F also appear to inhibit viral DNA synthesis by impeding the translocation of reverse transcriptase along template RNA. Because the functions of Vif and APOBEC3G/F proteins oppose each other, it is likely that fluctuations in the Vif-APOBEC balance may influence the natural history of HIV-1 infection, as well as viral sequence diversification and evolution. Given Vif's critical role in suppressing APOBEC3G/F function, it can be argued that pharmacologic strategies aimed at restoring the activity of these intrinsic anti-viral factors in the context of infected cells in vivo have clear therapeutic merit, and therefore deserve aggressive pursuit.

Figure 1

The genetic complexity of HIV-1. The six regulatory/accessory genes of (b) HIV-1 are not present in oncogenic retroviruses such as (a) avian leukosis virus (ALV). The proviruses of all replication-competent retroviruses are flanked by LTRs (pale grey) and encode gag, pol and env genes (dark grey). The direction of transcription from the 5′-LTR is indicated.

Figure 2

HIV-1 Vif induces the polyubiquitylation of APOBEC3G through recruitment of a cellular ubiquitin ligase. The known components of the cullin5 (Cul5)-elongin (Elo)B/C-Rbx ligase complex are indicated together with the identity of amino acid motifs that mediate important protein–protein interactions.

Figure 3

Inhibition of HIV-1 infection by APOBEC3G. (a) In the absence of Vif, A3G and A3F are packaged into progeny virions (producer) and transferred to (b) target cells. Infection is inhibited through a combination of cytidine deaminase-driven hypermutation and diminished reverse transcription. Refer to the text for further explanation.

Figure 4

Hypothetical representation of the balance between HIV-1 Vif and the APOBEC3 proteins. Viral benefit is represented by the purple line and the rate of mutation increases from left to right. It is possible that variations in Vif–A3G/F interactions (as well as in other APOBEC proteins) may contribute to viral sequence evolution, be beneficial for viral control in infected persons (for instances of robust viral control this could manifest as long-term survivor (LTS) or elite controller (EC) phenotypes), or alter rates of viral transmission (exposed uninfected person, EU). Effects on virus replication may, or may not, require editing. Potential causes of variation in cellular APOBEC3 protein activity are indicated in the box.