Hepatitis C Virus: NMR reveals replication essentials

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  • Published: Jun 1, 2015
  • Author: David Bradley
  • Channels: NMR Knowledge Base
thumbnail image: Hepatitis C Virus: NMR reveals replication essentials

Viral underpinnings

Interaction between the NS4B amphipathic helix, AH2, and charged lipid headgroups alters membrane morphology and AH2 oligomeric state — Implications for the Hepatitis C virus life cycle

NMR spectroscopy and other techniques underpin research at the University of Southampton into how changes in the cell membrane play a pivotal role in how the Hepatitis C virus replicates. By understanding the infection process, researchers hope to investigate how to block these changes and so facilitate the development of new drugs to combat the virus.

HCV infects an estimated 170 million people globally each year. It is a small virus, just 55 to 65 nanometres across, in the family Flaviviridae, and can be described as an enveloped, positive-sense single-stranded RNA virus. As the name suggests it causes the liver disease hepatitis C but also causes lymphoma in some people too. There is no vaccine for HCV and while research is underway into finding treatments, there are only two with US Food & Drug Administration approval and one of those must be used in conjunction with a signalling protein, an interferon.

Consistent roles

Researchers know that when HCV infects a host cell it uses one of its non-structural 4B protein, NS4B, to form a lipid-rich structure called the 'membranous web' that contains 'reaction centres' within which the virus can replicate unhindered by the antiviral weaponry of the host's immune system. Within NS4B, a peptide sequence, AH2, amphipathic helix, plays a crucial role in remodelling lipid membranes to form the membranous web. However, scientists do not know how AH2 makes these changes.

Now, Phil Williamson and colleagues have used solid-state phosphorus-31 nuclear magnetic resonance (NMR) spectroscopy (carried out at Southampton's Integrated Centre for NMR) in conjunction with molecular dynamics (MD) to reveal how AH2 interacts with negatively charged lipid membranes within the cell. "NMR spectra were recorded were recorded that reveal how AH2 remodels the bilayer," the team reports in the journal Biochimica et Biophysica Acta Biomembranes. They explain that it causes them to become more malleable, a property almost certainly important in reaction centre formation. When introduced into a cell membrane with neutral lipids, the team found that AH2 behaves differently, forming larger oligomeric complexes. These lead to limited deformation of the membrane, which they say is consistent with an independent role in the earlier stages of membranous web formation.

Understanding cellular hijack

"Now we begin to understand at the molecular level how HCV hijacks cellular membranes to aid its replications," explains Williamson. "We can use this information to help identify novel sites for therapeutic intervention to target HCV and similar viruses."

Chris McCormick adds that the research, "gives us an important lead on how changes in lipid content in the membranous web help drive membrane remodelling." He adds that, "The challenge for us now is to use the same interdisciplinary approach to link these activities with other maturation events seen inside the infected cell."

Williamson and McCormick worked with colleagues Esther Ashworth Briggs, Rafael Gomes, Malaz Elhussein, William Collier, Stuart Findlow and Syma Khalid.

Related Links

Biochim Biophys Acta 2015, 1848, 1671-1677: "Interaction between the NS4B amphipathic helix, AH2, and charged lipid headgroups alters membrane morphology and AH2 oligomeric state — Implications for the Hepatitis C virus life cycle"

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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