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Mouse adaptation determinants of poliovirus type 1 enhance viral uncoating
T Couderc1, F Delpeyroux, H Le Blay
1Unité de Neurovirologie et Régénération du Système Nerveux, Institut Pasteur, Paris, France.
Abstract:
Most poliovirus (PV) strains, such as PV type 1/Mahoney, cannot infect the mouse central nervous system. We previously identified two determinants of mouse adaptation of PV type 1/Mahoney at positions 22 and 31 of the viral capsid proteins VP1 and VP2, respectively (T. Couderc, J. Hogle, H. Le Blay, F. Horaud, and B. Blondel, J. Virol. 67:3808-3817, 1993). These residues are located on the interior surface of the capsid. In an attempt to understand the molecular mechanisms of adaptation of PV to mice, we investigated the effects of these two determinants on the viral multiplication cycle in a human cell line. Both determinants enhanced receptor-mediated conformational changes leading to altered particles of 135S, one of the first steps of uncoating, and viral internalization. Furthermore, the residue at position 22 of VP1 appears to facilitate RNA release. These results strongly suggest that these determinants could also facilitate conformational changes mediated by the PV murine receptor and internalization in the mouse nerve cell, thus allowing PV to overcome its host range restriction. Moreover, both mouse adaptation determinants are responsible for defects in the assembly of virions in human cells and affect the thermostability of the viral particles. Thus, these mouse adaptation determinants appear to control the balance between the viral capsid plasticity needed for the conformational changes in the early steps of infection and the structural requirements which are involved in the assembly and the stability of virions.
Insights
Two poliovirus (PV) capsid protein determinants enhance viral entry into human cells. These findings suggest mechanisms for PV mouse adaptation and host range expansion.
Area of Science:
- Virology
- Molecular Biology
- Infectious Diseases
Background:
- Poliovirus (PV) typically does not infect the mouse central nervous system.
- Previous research identified two key determinants (at VP1 position 22 and VP2 position 31) for PV mouse adaptation.
Purpose of the Study:
- To investigate the molecular mechanisms by which PV mouse adaptation determinants influence the viral multiplication cycle in human cells.
- To understand how these determinants affect early steps of viral infection, including receptor binding, conformational changes, and internalization.
Main Methods:
- Studied the effects of VP1 and VP2 determinants on PV multiplication in human cells.
- Analyzed receptor-mediated conformational changes, particle alterations (135S), viral internalization, and RNA release.
- Assessed virion assembly defects and particle thermostability in human cells.
Main Results:
- Both determinants enhanced receptor-mediated conformational changes and viral internalization in human cells.
- The VP1 determinant at position 22 facilitated RNA release.
- These determinants also caused defects in virion assembly and reduced particle thermostability in human cells.
Conclusions:
- The identified determinants likely facilitate PV entry into mouse nerve cells by promoting conformational changes and internalization, overcoming host range restrictions.
- These determinants balance viral capsid plasticity for infection initiation with structural stability required for assembly and virion integrity.