An Entropic Safety Catch Controls Hepatitis C Virus Entry and Antibody Resistance.

Stejskal, L.; Kalemera, M. D.; Palor, M.; Walker, L.; Daviter, T.; Lees, W. D.; Moss, D. S.; Kremyda-Vlachou, M.; Kozlakidis, Z.; Rosenberg, W.; Illingworth, C. J. R.; Shepherd, A. J.; Grove, J.

doi:10.1101/2020.11.11.377218

bioRxiv · 10.1101/2020.11.11.377218

An Entropic Safety Catch Controls Hepatitis C Virus Entry and Antibody Resistance.

Stejskal, L.·Kalemera, M. D.·Palor, M.·Walker, L.·Daviter, T.·Lees, W. D.·Moss, D. S.·Kremyda-Vlachou, M.·Kozlakidis, Z.·Rosenberg, W.·Illingworth, C. J. R.·Shepherd, A. J.·Grove, J.

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Abstract

E1 and E2 (E1E2), the entry proteins of Hepatitis C Virus (HCV), are unlike that of any other virus yet described, and the detailed molecular mechanisms of HCV entry/fusion remain unknown. Hypervariable region-1 (HVR-1) of E2 is a putative intrinsically disordered protein tail. Here, we demonstrate that HVR-1 has an autoinhibitory function that suppresses the activity of E1E2 on free virions; this is dependent on its conformational entropy. Crucially, to allow entry, this mechanism is turned off by host receptor interactions at the cell surface. Thus, HVR-1 is akin to a safety catch on E1E2 activity. Mutations that reduce conformational entropy in HVR-1, or genetic deletion of HVR-1, turn off the safety catch to generate hyper-reactive HCV that exhibits enhanced virus entry but is thermally unstable and acutely sensitive to neutralising antibodies. Therefore, the HVR-1 safety catch controls the efficiency of virus entry and maintains resistance to neutralising antibodies.

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Stejskal, L., Kalemera, M. D., Palor, M., Walker, L., Daviter, T., Lees, W. D., Moss, D. S., Kremyda-Vlachou, M., Kozlakidis, Z., Rosenberg, W., Illingworth, C. J. R., Shepherd, A. J., Grove, J.. 2020-11-11. An Entropic Safety Catch Controls Hepatitis C Virus Entry and Antibody Resistance.. https://doi.org/10.1101/2020.11.11.377218

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