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. 2000 Mar 14;97(6):2725-30.
doi: 10.1073/pnas.040575197.

Postexposure vaccination massively increases the prevalence of gamma-herpesvirus-specific CD8+ T cells but confers minimal survival advantage on CD4-deficient mice

G T Belz  1 , P G Stevenson, M R Castrucci, J D Altman, P C Doherty
Affiliations

Postexposure vaccination massively increases the prevalence of gamma-herpesvirus-specific CD8+ T cells but confers minimal survival advantage on CD4-deficient mice

G T Belz et al. Proc Natl Acad Sci U S A. .

Abstract

Mice that lack CD4(+) T cells remain clinically normal for more than 60 days after respiratory challenge with the murine gamma-herpesvirus 68 (gammaHV-68), then develop symptoms of a progressive wasting disease. The gammaHV-68-specific CD8(+) T cells that persist in these I-A(b-/-) mice are unable to prevent continued, but relatively low level, virus replication. Postexposure challenge with recombinant vaccinia viruses expressing gammaHV-68 lytic cycle epitopes massively increased the magnitude of the gammaHV-68-specific CD8(+) population detectable by staining with tetrameric complexes of MHC class I glycoprotein + peptide, or by interferon-gamma production subsequent to in vitro restimulation with peptide. The boosting effect was comparable for gammaHV-68-infected I-A(b-/-) and I-A(b+/+) mice within 7 days of challenge, and took more than 110 days to return to prevaccination levels in the I-A(b+/+) controls. Although the life-span of the I-A(b-/-) mice was significantly increased, there was no effect on long-term survival. A further boost with a recombinant influenza A virus failed to improve the situation. Onset of weight loss was associated with a decline in gammaHV-68-specific CD8(+) T cell numbers, though it is not clear whether this was a cause or an effect of the underlying pathology. Even very high levels of virus-specific CD8(+) T cells thus provide only transient protection against the uniformly lethal consequences of gammaHV-68 infection under conditions of CD4(+) T cell deficiency.

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Figures

Figure 1
Figure 1
Virus-specific CD8+ T cells in spleen populations from γHV-68-infected I-Ab+/+ mice challenged with recombinant vaccinia viruses. The B6 mice were challenged i.p. with 3 × 107 pfu of the vacc-p56, vacc-p79, or vacc-LCMVb recombinants 1 mo after i.n. infection with 600 pfu of γHV-68. Spleen populations were enriched for the CD8+ set and stained with the p56Db (A–C) and p79Kb (D and E) tetramers. The results are for a representative animal from each group, with the percent values in the quadrants being for the total lymphocyte population. Cumulated data from three comparable experiments are presented in Table 1.
Figure 2
Figure 2
Persistence of p56- and p79-specific CD8+ T cells in boosted, γHV-68-infected I-Ab+/+ mice. The mice were infected i.n. with γHV-68 1 mo prior to i.p. challenge with the recombinant vaccinia viruses, as detailed in the Fig. 1 legend. Each data point shows the mean ± SE for three individuals. The titers of latent γHV-68 in the spleen were minimal for all groups.
Figure 3
Figure 3
The γHV-68-specific CD8+ T cell responses following secondary challenge of persistently infected I-Ab−/− mice. The mice were infected with γHV-68, then challenged with the vacc-p56, vaccp79, and vacc-LCMVb recombinants, as described in the Fig. 1 legend. The results are given as mean ± SE for virus-specific CD8+ T cells in the spleens of three mice. Those sampled on day 63 after vaccinia (day 91 after γHV-68) were clinically affected and provide some of the virus titer results presented in Table 2.
Figure 4
Figure 4
Survival profiles for γHV-68-infected I-Ab−/− mice boosted with recombinant vaccinia viruses. The I-Ab−/− mice were infected i.n. with γHV-68 and boosted with the recombinant vaccinia viruses, as described in the Fig. 1 legend. The survival profiles were then determined for groups of 20 mice, with any animals that were severely affected being terminated. Vaccinia virus infection alone did not cause any mortality in I-Ab−/− mice, and the pattern of illness in the vacc-LCMVb group was indistinguishable from that for other controls given γHV-68 alone (data not shown). The mice given vacc-p56 lived significantly longer (P = 0.0003 by logrank test) than those injected with vacc-p79 or vacc-LCMVb.
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