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J. Virol. doi:10.1128/JVI.01674-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Amino Acid Substitutions in the S2 Subunit of Mouse Hepatitis Virus Variant V51 Encode Determinants of Host Range Expansion

Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7290; Department of Epidemiology, School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7435

^* To whom correspondence should be addressed. Email: rbaric{at}email.unc.edu.

	Abstract

We previously described Mouse Hepatitis Virus (MHV) variant V51 derived from a persistent infection of murine DBT cells with an expanded host range (Baric et al, J. Virol. 73:638-49). Sequencing of the V51 Spike gene, the mediator of virus entry, revealed 13 amino acid substitutions relative to the originating MHV A59 strain. Seven substitutions were located in the amino-terminal S1 cleavage subunit and six in the carboxy-terminal S2 cleavage subunit. Using targeted RNA recombination, a panel of recombinant viruses was used to map the mediators of host range to the six substitutions in S2, with a subgroup of four changes of particular interest. This subgroup maps to two previously identified domains within S2, a putative fusion peptide and a heptad repeat, both conserved features of Class I fusion proteins. In addition to altered host range, V51 also displayed utilization of CEACAM1a, the high affinity receptor for A59. Interestingly, a recombinant with S1 from A59 and S2 from V51 was severely debilitated in its ability to productively infect cells via CEACAM1a, while the inverse recombinant was not. This suggests that the S2 substitutions exert powerful effects on the fusion trigger that normally passes from S1 to S2. These novel findings play against the existing data that suggests MHV host range determinants are located in the S1 subunit, which harbors the receptor binding domain, or coordinating changes in both S1 and S2. Mounting evidence also implicates the Class I fusion mechanism may possess some innate plasticity that regulates viral host range.

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