Host APOBEC3G protein inhibits HCV replication through direct binding at NS3

PLoS One. 2015 Mar 26;10(3):e0121608. doi: 10.1371/journal.pone.0121608. eCollection 2015.

Abstract

Human APOBEC3G (hA3G) is a cytidine deaminase that restricts replication of certain viruses. We have previously reported that hA3G was a host restriction factor against hepatitis C virus (HCV) replication, and hA3G stabilizers showed a significant inhibitory activity against HCV. However, the molecular mechanism of hA3G against HCV remains unknown. We show in this study that hA3G's C-terminal directly binds HCV non-structural protein NS3 at its C-terminus, which is responsible for NS3's helicase and NTPase activity. Binding of hA3G to the C-terminus of NS3 reduced helicase activity, and therefore inhibited HCV replication. The anti-HCV mechanism of hA3G appeared to be independent of its deamination activity. Although early stage HCV infection resulted in an increase in host hA3G as an intracellular response against HCV replication, hA3G was gradually diminished after a long-term incubation, suggesting an unknown mechanism(s) that protects HCV NS3 from inactivation by hA3G. The process represents, at least partially, a cellular defensive mechanism against HCV and the action is mediated through a direct interaction between host hA3G and HCV NS3. We believe that understanding of the antiviral mechanism of hA3G against HCV might open an interesting avenue to explore hA3G stabilizers as a new class of anti-HCV agents.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • APOBEC-3G Deaminase
  • Cell Line
  • Cytidine Deaminase / metabolism*
  • Hepacivirus / physiology*
  • Hepatitis C / metabolism*
  • Hepatitis C / pathology
  • Hepatitis C / virology*
  • Host-Pathogen Interactions*
  • Humans
  • Intracellular Space / metabolism
  • Models, Molecular
  • Protein Binding
  • Protein Interaction Maps
  • Viral Nonstructural Proteins / metabolism*
  • Virus Replication*

Substances

  • NS3 protein, hepatitis C virus
  • Viral Nonstructural Proteins
  • APOBEC-3G Deaminase
  • APOBEC3G protein, human
  • Cytidine Deaminase

Grant support

The work was supported by the National Natural Science Foundation, China (81321004, JD Jiang; 81322050, ZG Peng; 81173101, ZG Peng), National Mega-Project for "R&D for Innovative drugs", Ministry of Science and Technology, China (2012ZX09301-002-001, JD Jiang), Ministry of Education, China (NCET-12-0072, ZG Peng). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.