We read with great interest the recent article by Peng et al.,1 in which the authors investigated the role of APOBEC3G (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3G), also named hA3G, in the regulation of hepatitis C virus (HCV) replication. In particular, the authors demonstrated that silencing of hA3G increased the rate of HCV replication in infected Huh7.5 cells. Furthermore, the study highlighted that hA3G stabilization by RN-5 [N,N0-(dimethylbipheny1-4, 40-diyl) dibenzenesulfonamide] or IMB-26 [([3-(a-bromopropyl) amino-4-methoxy benzene] formyl (30,40,50-trimethoxybenzene) amide] increased the expression of the intracellular hA3G, resulting in the inhibition of HCV replication.
The hA3G belongs to the APOBEC3 family of proteins, which are the best-characterized type of editing enzymes able to restrict the infectivity of human immunodeficiency virus-1.2 However, the most frequent type of editing in humans is mediated by three adenosine deaminases acting on RNA (ADARs), ADAR1-3, which convert adenosine (A) to inosine (I) in double-stranded RNA.3 Interestingly, the ADAR enzymes also play important roles during viral infection by acting as proviral or antiviral factors.3
It has been reported that ADAR1 silencing in hepatoma cells expressing HCV replicons may stimulate the expression of HCV RNA.4 In addition, it has been suggested that ADAR1 may act as an antiviral factor in the context of HCV infection through a combination of direct and indirect mechanisms.3
We recently investigated the expression of ADAR1 in Huh7.5 cells infected using the in vitro HCV infection and replication JFH1 (Japanese fulminant hepatitis-1) model. We demonstrated (Fig. 1) that HCV infection specifically modulates the ratio between the two major ADAR1 isoforms: p150-kDa and p110-kDa. In particular, HCV up-regulated the 150-kDa isoform, which is the classical interferon-inducible isoform, whereas the 110-kDa constitutive isoform seems not significantly modified.
Taken together, these studies demonstrate that during HCV infection at least two host factors, hA3G and ADAR1, are activated. Despite the antiviral action of hA3G that has been recently shown by Peng et al., we suggest that hA3G and ADARs require further investigation, because they can disclose additive or opposite effects during HCV infection.
The involvement of other host editing enzymes, such as ADARs, can introduce an additional step of complexity in the HCV infection and its related fibrogenic and oncogenic properties. Moreover, the comprehension of the specific role played by these enzymes in the HCV life-cycle, and in the regulation of virus–host intracellular interactions, can provide relevant information in designing novel potential safe and efficient molecular therapies.