Surprisingly, S598 Q600Y still did not undergo sequence diversification in mice that survived the rJ.S W513R+Q600Y infection ( Table 2) . This result was unexpected, as the majority of CTL in the rJ.S W513R+Q600Y -infected CNS specifically target the magnitude, unidirectional cross-reactivity. Representative dot plots demonstrating the frequency of epitope-specific CD8 T cells in a mouse infected with rJ (top panels) or rJ.S Q600Y (bottom panels). Numbers represent the frequency of epitope-specific CD8 T cells among total CD8 T cells recovered from the brains of mice 7 days p.i. (E) Summaries of the frequency (left panel) and absolute number (right panel) of epitope-specific CD8 T cells recovered from the brains of rJ and rJ.S Q600Y -infected mice 7 days p.i. Data shown in D represent mean6SEM for 4 independent experiments. doi:10.1371/journal.ppat.1000186.g002 S598 Q600Y determinant and exhibit high functional avidity ( Figure 3A-C) . One possible explanation for this result is that S598 is not as plastic as S510, even though both determinants are derived from a region of the spike gene that is hypervariable and even deleted in some strains of MHV [32] .