Induction of APOBEC3 family proteins, a defensive maneuver underlying interferon-induced anti–HIV-1 activity

Abstract

Apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like 3G (APOBEC3G), a cytidine deaminase, is a recently recognized innate intracellular protein with lethal activity against human immunodeficiency virus (HIV). Packaged into progeny virions, APOBEC3G enzymatic activity leads to HIV DNA degradation. As a counterattack, HIV virion infectivity factor (Vif) targets APOBEC3G for proteasomal proteolysis to exclude it from budding virions. Based on the ability of APOBEC3G to antagonize HIV infection, considerable interest hinges on elucidating its mechanism(s) of regulation. In this study, we provide the first evidence that an innate, endogenous host defense factor has the potential to promote APOBEC3G and rebuke the virus-mediated attempt to control its cellular host. We identify interferon (IFN)-α as a potent inducer of APOBEC3G to override HIV Vif neutralization of APOBEC3 proteins that pose a threat to efficient macrophage HIV replication. Our data provide a new dimension by which IFN-α mediates its antiviral activity and suggest a means to render the host nonpermissive for viral replication.

HIV-1 Gag-Virus-Like Particles Inhibit HIV-1 Replication in Dendritic Cells and T Cells through IFN-α-Dependent Upregulation of APOBEC3G and 3F

“…IFN-α exerts its antiviral activity through multiple mechanisms besides A3 induction, such as the RNA-dependent protein kinase/eukaryotic initiation factor 2α pathway, oligoadenylate synthetase/RNase L pathway and RNA deaminases [47]. However, Peng et al [41] showed that depletion of A3G by small interfering RNA (siRNA) resulted in loss of the ability of IFN-α to completely inhibit HIV replication, confirming that A3 is a key downstream anti-HIV mechanism induced by IFN-α.…”

“…IFN-α significantly enhances the expression of A3G/3F at the transcriptional level and promotes anti-HIV-1 activity [39,40,41]. A3 levels in human DCs increase and restrict HIV-1 replication during DC maturation or after treatment with IFN-α [42].…”

Modeling the intracellular dynamics for Vif-APO mediated HIV-1 virus infection

“…Besides human, mice also expresses its own A3G, but HIV-1 Vif can not efficiently form complex with it [53]. APO has already been found related to innate defense mechanisms in primary human T cells [33], macrophages [46] and immature dendritic cells [47]. There are evidences for hepatitis B virus and hepatitis C virus to interact with A3G and/or A3F [48,49].…”

“…Therefore, besides tuning parameters directly down regulating viral RNA and Tat α ) to lower Tat level will significantly reduce the virion proliferation and restore the innate defense mechanism mediated by APO (Figure 4 (b)). The Vif-APO related virus-host intracellular dynamic system modeled here was found to widely exist in a number of cell types and viruses [33,[46][47][48][49]. APOBEC is a large family of proteins.…”

Powerful mutators lurking in the genome

“…The HIV-1/ A3F/A3G example parallels perfectly that of ADAR-1L editing of viral RNA. With the word parallel in mind, it is now clear that the A3G gene is strongly upregulated by type I and type II interferons, both in vitro and in vivo (Bonvin et al 2006;Peng et al 2006;Tanaka et al 2006). Viral hypermutation indicates that nature, as opposed to Nature, has wised up to the fact that blitzkrieg mutation is yet another efficient way of fighting viruses.…”