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The immunoevasive function encoded by the mouse cytomegalovirus gene m152 protects the virus against T cell control in vivo.

Krmpotic A, Messerle M, Crnkovic-Mertens I, Polic B, Jonjic S, Koszinowski UH - J. Exp. Med. (1999)

Bottom Line: Immunity. 6:57-66).This attenuating effect is lifted by reinsertion of the gene into the mutant.These results prove that MHC-reactive functions protect CMVs against attack by CD8(+) T lymphocytes in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Histology, Faculty of Medicine, University of Rijeka, 51000 Rijeka, Croatia.

ABSTRACT
Cytomegaloviruses encode numerous functions that inhibit antigen presentation in the major histocompatibility complex (MHC) class I pathway in vitro. One example is the mouse cytomegalovirus (MCMV) glycoprotein gp40, encoded by the m152 gene, which selectively retains murine but not human MHC class I complexes in the endoplasmic reticulum-Golgi intermediate compartment/cis-Golgi compartment (Ziegler, H., R. Thäle, P. Lucin, W. Muranyi, T. Flohr, H. Hengel, H. Farrell, W. Rawlinson, and U.H. Koszinowski. 1997. Immunity. 6:57-66). To investigate the in vivo significance of this gene function during MCMV infection of the natural host, we constructed recombinants of MCMV in which the m152 gene was deleted, as were the corresponding virus revertants. We report on the following findings: Deletion of the m152 gene has no effect on virus replication in cell culture, whereas after infection of mice, the m152-deficient virus replicates to significantly lower virus titers. This attenuating effect is lifted by reinsertion of the gene into the mutant. Mutants and revertants grow to the same titer in animals deprived of the function targeted by the viral gene function, namely in mice deficient in beta2-microglobulin, mice deficient in the CD8 molecule, and mice depleted of T cells. Upon adoptive transfer of naive lymphocytes into infected mice, the absence of the m152 gene function sensitizes the virus to primary lymphocyte control. These results prove that MHC-reactive functions protect CMVs against attack by CD8(+) T lymphocytes in vivo.

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Reduced virulence and replication capacity of the m152 deletion mutant in vivo. (A) Newborn BALB/c mice were inoculated with 100 PFU i.p. of wild-type (w.t.) MCMV (○), ΔMC95.24 (filled gray triangles), or rMC96.27 (•) virus 12 h post partum, and their survival was monitored daily. (B) Newborn BALB/c mice were infected as shown in A, and virus titers were determined 8 d after infection. Data represent the mean value of at least five mice.
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Figure 4: Reduced virulence and replication capacity of the m152 deletion mutant in vivo. (A) Newborn BALB/c mice were inoculated with 100 PFU i.p. of wild-type (w.t.) MCMV (○), ΔMC95.24 (filled gray triangles), or rMC96.27 (•) virus 12 h post partum, and their survival was monitored daily. (B) Newborn BALB/c mice were infected as shown in A, and virus titers were determined 8 d after infection. Data represent the mean value of at least five mice.

Mentions: Considering the fact that three different MCMV genes affect nascent MHC molecules and that m152 merely represents the gene that is expressed first, it was not clear whether or not the deletion of this gene would have any detectable impact on the susceptibility of the virus to immune control in vivo. Whereas adult mice control the infection with tissue culture–derived wild-type MCMV effectively, young mice allow virus replication to high titers 3940. To detect even minor differences in virulence due to deletion of the single m152 gene, we assayed virus replication in neonatal mice. To avoid the potential influence of marker gene products on the biological properties of mutant viruses, the in vivo experiments were performed mainly with the m152 deletion mutant ΔMC95.24 and the revertant virus rMC96.27, although the other mutants gave comparable results (data not shown). Neonatal mice were injected with 100 PFU of the m152 deletion mutant, the revertant virus, or wild-type MCMV and monitored for 30 d. After infection with wild-type MCMV or revertant virus, 53 and 75%, respectively, of animals succumbed to infection (Fig. 4 A). In contrast, infection with the m152 deletion mutant was survived by the majority of mice (25% mortality). With respect to clinical signs, all three groups of mice exhibited during the first week of infection significant runting and a general failure to thrive compared with mock-infected controls. By 14–20 d after infection, however, most animals that survived the infection with the m152 deletion mutant had recovered. In contrast, clinical signs persisted throughout the course of observation for wild-type MCMV and revertant virus–infected mice. The different disease courses correlated with the body weights of infected mice. On day 26 after infection, the average body weight of mice that survived infection with ΔMC95.24 was comparable to that of the control group (9.79 ± 1.86 and 10.9 ± 1.16 g, respectively), whereas mice infected with the revertant virus still appeared runted (7.04 ± 1.70 g; data not shown).


The immunoevasive function encoded by the mouse cytomegalovirus gene m152 protects the virus against T cell control in vivo.

Krmpotic A, Messerle M, Crnkovic-Mertens I, Polic B, Jonjic S, Koszinowski UH - J. Exp. Med. (1999)

Reduced virulence and replication capacity of the m152 deletion mutant in vivo. (A) Newborn BALB/c mice were inoculated with 100 PFU i.p. of wild-type (w.t.) MCMV (○), ΔMC95.24 (filled gray triangles), or rMC96.27 (•) virus 12 h post partum, and their survival was monitored daily. (B) Newborn BALB/c mice were infected as shown in A, and virus titers were determined 8 d after infection. Data represent the mean value of at least five mice.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2195686&req=5

Figure 4: Reduced virulence and replication capacity of the m152 deletion mutant in vivo. (A) Newborn BALB/c mice were inoculated with 100 PFU i.p. of wild-type (w.t.) MCMV (○), ΔMC95.24 (filled gray triangles), or rMC96.27 (•) virus 12 h post partum, and their survival was monitored daily. (B) Newborn BALB/c mice were infected as shown in A, and virus titers were determined 8 d after infection. Data represent the mean value of at least five mice.
Mentions: Considering the fact that three different MCMV genes affect nascent MHC molecules and that m152 merely represents the gene that is expressed first, it was not clear whether or not the deletion of this gene would have any detectable impact on the susceptibility of the virus to immune control in vivo. Whereas adult mice control the infection with tissue culture–derived wild-type MCMV effectively, young mice allow virus replication to high titers 3940. To detect even minor differences in virulence due to deletion of the single m152 gene, we assayed virus replication in neonatal mice. To avoid the potential influence of marker gene products on the biological properties of mutant viruses, the in vivo experiments were performed mainly with the m152 deletion mutant ΔMC95.24 and the revertant virus rMC96.27, although the other mutants gave comparable results (data not shown). Neonatal mice were injected with 100 PFU of the m152 deletion mutant, the revertant virus, or wild-type MCMV and monitored for 30 d. After infection with wild-type MCMV or revertant virus, 53 and 75%, respectively, of animals succumbed to infection (Fig. 4 A). In contrast, infection with the m152 deletion mutant was survived by the majority of mice (25% mortality). With respect to clinical signs, all three groups of mice exhibited during the first week of infection significant runting and a general failure to thrive compared with mock-infected controls. By 14–20 d after infection, however, most animals that survived the infection with the m152 deletion mutant had recovered. In contrast, clinical signs persisted throughout the course of observation for wild-type MCMV and revertant virus–infected mice. The different disease courses correlated with the body weights of infected mice. On day 26 after infection, the average body weight of mice that survived infection with ΔMC95.24 was comparable to that of the control group (9.79 ± 1.86 and 10.9 ± 1.16 g, respectively), whereas mice infected with the revertant virus still appeared runted (7.04 ± 1.70 g; data not shown).

Bottom Line: Immunity. 6:57-66).This attenuating effect is lifted by reinsertion of the gene into the mutant.These results prove that MHC-reactive functions protect CMVs against attack by CD8(+) T lymphocytes in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Histology, Faculty of Medicine, University of Rijeka, 51000 Rijeka, Croatia.

ABSTRACT
Cytomegaloviruses encode numerous functions that inhibit antigen presentation in the major histocompatibility complex (MHC) class I pathway in vitro. One example is the mouse cytomegalovirus (MCMV) glycoprotein gp40, encoded by the m152 gene, which selectively retains murine but not human MHC class I complexes in the endoplasmic reticulum-Golgi intermediate compartment/cis-Golgi compartment (Ziegler, H., R. Thäle, P. Lucin, W. Muranyi, T. Flohr, H. Hengel, H. Farrell, W. Rawlinson, and U.H. Koszinowski. 1997. Immunity. 6:57-66). To investigate the in vivo significance of this gene function during MCMV infection of the natural host, we constructed recombinants of MCMV in which the m152 gene was deleted, as were the corresponding virus revertants. We report on the following findings: Deletion of the m152 gene has no effect on virus replication in cell culture, whereas after infection of mice, the m152-deficient virus replicates to significantly lower virus titers. This attenuating effect is lifted by reinsertion of the gene into the mutant. Mutants and revertants grow to the same titer in animals deprived of the function targeted by the viral gene function, namely in mice deficient in beta2-microglobulin, mice deficient in the CD8 molecule, and mice depleted of T cells. Upon adoptive transfer of naive lymphocytes into infected mice, the absence of the m152 gene function sensitizes the virus to primary lymphocyte control. These results prove that MHC-reactive functions protect CMVs against attack by CD8(+) T lymphocytes in vivo.

Show MeSH
Related in: MedlinePlus