If CTL recognizing S598 Q600Y exhibit high functional avidity in vivo, they should protect from CTL escape in S510 and might select for S598 Q600Y CTL escape variants. Diversification at S510 is observed in pups infected with neurovirulent JHMV at 10 days of age and nursed by JHMV-immune dams [27] . These mice are largely protected from developing acute lethal encephalitis, but a variable percentage (30-90%) later develop a demyelinating encephalomyelitis. Infectious virus isolated from these mice with late onset clinical disease is mutated in S510, resulting in enhanced virus replication [20] , with demyelination occurring during the process of virus clearance [28] . Thus, we next infected maternal antibody-protected suckling mice with rJ or rJ.S Q600Y viruses and monitored persistently infected mice for the development of clinical signs for 60 days post infection (p.i.). The presence of the highly immunogenic S598 Q600Y epitope did not protect mice from acute encephalitis ( Figure 3E ), perhaps because the presence of the improved S598 epitope was accompanied by a diminished response to S510 ( Figure 2D ). However, we found that among survivors (defined as survival past day 14 p.i.) there was a significant reduction in the incidence of clinical disease as well as in the development of CTL escape in S510 (Table 1) . Additionally, S598 Q600Y did not undergo CTL escape in mice persistently infected with rJ.S Q600Y , even though single nucleotide changes in the region of the S glycoprotein gene encoding the S598 determinant could potentially result in fifty-one CTL escape mutations. Thus, as expected, the ''improved'' S598 Q600Y epitope was protective in vivo in infected mice, likely because S598 Q600Yspecific CTL are present in higher numbers and exhibit higher functional avidity than the native S598-specific response.