Since this lack of mutation at S598 Q600Y might reflect enhanced suppression of virus replication mediated by co-dominant CTL responses directed against S510 and S598 Q600Y , we developed a recombinant virus encoding S598 Q600Y in the context of a common S510 CTL escape mutation, S510 W513R (rJ.S W513R+Q600Y , Figure 2A ). The CTL response is predicted to be largely directed at S598 Q600Y in mice infected with this virus. The W513R mutation (position 4 substitution in S510 epitope, CSLRNGPHL) occurs in 13% of all CTL escape variants [19, 20, 22, 29, 30] , and completely abrogates native S510 CTL recognition [31] . We verified that virusspecific CTL responses were focused on S598 Q600Y in adult B6 mice infected with rJ.S W513R+Q600Y ( Figure 3F ). To examine the phenotype of the S598 Q600Y /S510 W513R double mutant, we infected antibody-protected suckling B6 mice with this virus and appropriate controls and monitored mice for survival ( Figure 3G ). As expected, 93.3% of mice infected with rJ survived the acute infection (day 0-14 p.i.). All mice infected with rJ.S W513R developed fatal encephalitis but, in marked contrast, 66.6% of mice infected with rJ.S W513R+Q600Y survived. We also found that survival correlated with virus clearance ( Figure 3H ). Relative to rJ-infected mice, replication was suppressed in mice infected with virus encoding the S598 Q600Y epitope and greatly elevated in mice infected with rJ.S W513R . In mice infected with rJ.S W513R+Q600Y , virus titers were intermediate between rJ and rJ.S W513R . Thus, the presence of the heteroclitic S598 Q600Y determinant contributed to suppression of virus replication and to increased survival, even when the highmagnitude, high-avidity CTL response to S510 was largely abrogated.