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

• DOI: 10.1002/hep.24160
• Publication Date: 2011-01-10T18:07:53Z
• Authors: Zong-Gen Peng; Zhi-Yun Zhao; Yan-Ping Li; Yu-Ping Wang; Lan-Hu Hao; Bo Fan; Yu-Huan Li; Yue-Ming Wang; Yong-Qiang Shan; Yan-Xing Han; Yan-Ping Zhu; Jian-Rui Li; Xue-Fu You; Zhuo-Rong Li; Jian-Dong Jiang
• Keywords: 0303 health sciences; APOBEC-1 Deaminase; Hepacivirus; Anisoles; Virus Replication; Hepatitis C; Immunity, Innate; Cell Line; 3. Good health; Mice; 03 medical and health sciences; Cytidine Deaminase; Benzamides; Animals; Humans; RNA Editing

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(+) 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. (HEPATOLOGY 2011;)