New research from the University of Southampton has identified how changes in the cell membrane¹ play a pivotal role in how the Hepatitis C virus replicates³. By understanding this process, the researchers hope to investigate how to prevent the changes and potentially develop therapeutic⁴ drugs to combat the Hepatitis C virus (HCV), which infects an estimated 170 million people globally.

 

When HCV infects a cell it uses one of its proteins, NS4B, to form a lipid-rich structure called the 'membranous⁵ web'. This structure contains 'reaction centres', where the virus can replicate² protected from the host cell's antivirus defences. 

 

Within NS4B, the AH2 peptide plays a crucial role in remodelling⁶ lipid membranes⁷ to form the membranous web. However, it is not understood how AH2 causes these changes.

 

Using nuclear magnetic resonance⁸ (NMR) spectroscopy in conjunction with molecular⁹ dynamics¹⁰ (MD), Southampton researchers showed that AH2 interacts with negatively charged lipid membranes within the cell. It causes them to become more malleable¹¹, a property almost certainly important in reaction centre formation. When introduced into membranes with non-charged lipids, AH2 behaved differently, forming larger complexes resulting in limited deformation¹² of the membrane, consistent with a separate role in early steps of membranous web formation. 

 

Co-author of the study Dr Phil Williamson, Lecturer in Biological Sciences, says: "Now we begin to understand at the molecular level how HCV hijacks¹³ cellular¹⁴ membranes to aid its replications, we can use this information to help identify novel sites for therapeutic intervention¹⁵ to target HCV and similar viruses."

 

Co-author Dr Chris McCormick, from Medicine at the University of Southampton, adds: "This gives us an important lead on how changes in lipid content in the membranous web help drive membrane remodelling. 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."

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