Host apolipoprotein b messenger RNA-editing enzyme catalytic polypeptide-like 3G is an innate defensive factor and drug target against hepatitis C virus

Abstract

Host cellular factor apolipoprotein B messenger RNA (mRNA)-editing enzyme catalytic polypeptide-like 3G (hA3G) is a cytidine deaminase that inhibits a group of viruses including human immunodeficiency virus-1 (HIV-1). In the continuation of our research on hA3G, we found that hA3G stabilizing compounds significantly inhibited hepatitis C virus (HCV) replication. Therefore, this study investigated the role of hA3G in HCV replication. Introduction of external hA3G into HCV-infected Huh7.5 human hepatocytes inhibited HCV replication; knockdown of endogenous hA3G enhanced HCV replication. Exogenous HIV-1 virion infectivity factor (Vif) decreased intracellular hA3G and therefore enhanced HCV proliferation, suggesting that the presence of Vif might be an explanation for the HIV-1/HCV coinfection often observed in HIV-1(1) individuals. Treatment of the HCV-infected Huh7.5 cells with RN-5 or IMB-26, two known hA3G stabilizing compounds, increased intracellular hA3G and accordingly inhibited HCV replication. The compounds inhibit HCV through increasing the level of hA3G incorporated into HCV particles, but not through inhibiting HCV enzymes. However, G/A hypermutation in the HCV genome were not detected, suggesting a new antiviral mechanism of hA3G in HCV, different from that in HIV-1. Stabilization of hA3G by RN-5 was safe in vivo. Conclusion: hA3G appears to be a cellular restrict factor against HCV and could be a potential target for drug discovery.

The preferred nucleotide contexts of the AID/APOBEC cytidine deaminases have differential effects when mutating retrotransposon and virus sequences compared to host genes

“…This resistant cluster includes many viral genomes, such as Human Herpesvirus 1 [31], and hepatitis C Virus [35]. Curiously, this cluster includes the Epstein-Barr Virus, suggesting that this virus may have evolved resistance to mutations by both APOBECs and AID.…”

Synthesis and antiviral activity of a novel class of (5-oxazolyl)phenyl amines

“…HCV virus stock was prepared as previously reported [37,38]. The African green monkey kidney cells (Vero), coxsackie viruses (Coxsackie virus B3 Nancy strain and Coxsackie virus B6 Schmitt strain) were acquired from the Institute of Virology, Chinese Academy of Preventive Medicine (Beijing, China).…”

The Role of Cytidine Deaminases on Innate Immune Responses against Human Viral Infections

“…Considering that A3G targets ssDNA, such lack of hypermutation is expected for HCV, which presents exclusively RNA as genomic material during all phases of its replication. Interestingly, it has also been shown that the presence of exogenous HIV-1 Vif led to an intracellular decrease of A3G and consequently to an increase of HCV replication, suggesting the involvement of Vif in the HIV-1/HCV coinfection [220]. …”

“…Treatment of HCV-infected Huh7.5 cells with two stabilizing components of APOBEC3G, which increased its intracellular levels, inhibited HCV replication [220]. …”