Infected cell protein (ICP)47 enhances herpes simplex virus neurovirulence by blocking the CD8+ T cell response - PubMed (original) (raw)

Infected cell protein (ICP)47 enhances herpes simplex virus neurovirulence by blocking the CD8+ T cell response

K Goldsmith et al. J Exp Med. 1998.

Abstract

The herpes simplex virus (HSV) infected cell protein (ICP)47 blocks CD8+ T cell recognition of infected cells by inhibiting the transporter associated with antigen presentation (TAP). In vivo, HSV-1 replicates in two distinct tissues: in epithelial mucosa or epidermis, where the virus enters sensory neurons; and in the peripheral and central nervous system, where acute and subsequently latent infections occur. Here, we show that an HSV-1 ICP47- mutant is less neurovirulent than wild-type HSV-1 in mice, but replicates normally in epithelial tissues. The reduced neurovirulence of the ICP47- mutant was due to a protective CD8+ T cell response. When compared with wild-type virus, the ICP47- mutant expressed reduced neurovirulence in immunologically normal mice, and T cell-deficient nude mice after reconstitution with CD8+ T cells. However, the ICP47- mutant exhibited normal neurovirulence in mice that were acutely depleted of CD8+ T cells, and in nude mice that were not reconstituted, or were reconstituted with CD4+ T cells. In contrast, CD8+ T cell depletion did not increase the neurovirulence of an unrelated, attenuated HSV-1 glycoprotein (g)E- mutant. ICP47 is the first viral protein shown to influence neurovirulence by inhibiting CD8+ T cell protection.

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Figures

Figure 1

Figure 1

Generation of an HSV-1 ICP47 deletion mutant. The genome of HSV-1 is depicted in the upper panel of the figure. A 100- nucleotide deletion in the HSV US12 gene, which encodes ICP47, was created. The deletion removes the ICP47 start codon and two downstream ATG codons, but does not affect the promoter of the adjacent US11 gene. Cells were cotransfected with a plasmid containing the deletion, and viral DNA derived from HSV-1 (strain F). Virus progeny were screened for the mutation by performing PCR on samples of viral DNA. A virus, denoted F-ICP47Δ, contained the deletion in the US12 gene. A rescued derivative of F-ICP47Δ, denoted F-ICP47ΔR, was produced by cotransfecting cells with F-ICP47Δ DNA and a plasmid containing the wild-type US12 gene. In the lower panel, cells were infected with wild-type HSV-1, F-ICP47Δ, or F-ICP47ΔR, then radiolabeled with [35S]methionine. ICP47 was immunoprecipitated from cell extracts using a rabbit anti-ICP47 serum, and US11 protein was immunoprecipitated using an anti-US11 serum.

Figure 2

Figure 2

ICP47 enhances neurovirulence in mice. In 3 experiments, groups of 10 female A/J mice were depleted of CD8+ T cells by injection of anti-CD8 mAb (solid bars), or were mock depleted by injection of control mAb (gray bars). The mice received uniocular corneal infections with 105 PFU of wild-type HSV-1 F strain, F-ICP47Δ, or F-ICP47ΔR, or F-gEβ. The survival rate was determined after a 30-d observation period, although all deaths occurred 12–14 d after infection. The *** indicates that the survival rate was significantly increased (P < 0.001) in immunologically normal mice infected with the F-ICP47Δ deletion mutant when compared with one of the following: CD8+ T cell–depleted mice infected with F-ICP47Δ; immunologically normal mice infected with wild-type F; or immunologically normal mice infected with F-ICP47ΔR.

Figure 3

Figure 3

ICP47 does not enhance neurovirulence in T cell– deficient mice. Groups of six BALB/c athymic nude mice received corneal infections with various doses of F-ICP47Δ (▴) or F-ICP47ΔR (□). The mortality rate was observed over a 30-d observation period. The symbols represent the percentage of mortality at each infectious dose. The linear regression lines are shown for each data set. There is no significant difference in the slopes (P = 0.6604) or the elevations and intercepts (P = 0.3738) of the two lines.

Figure 4

Figure 4

Adoptive transfer of CD8+, but not CD4+, T cells inhibits neurovirulence of the ICP47− mutant in nude mice. Groups of five BALB/c athymic nude mice received corneal infections with 105 PFU of F-ICP47Δ HSV-1 (A), or F-ICP47ΔR HSV-1 (B). 6 d later, the control group (□) received no cells, or the mice received 1.5 × 107 lymph node cells from HSV-1– infected euthymic BALB/c mice that were highly enriched for CD4+ (▵) CD8+ (○) T lymphocytes. Survival of the recipient mice was followed through a 30-d observation period. Adoptive transfer of CD8+ cells conferred a significant survival advantage for mice infected with the F-ICP47Δ strain (P = 0.0186), but not for mice infected with the F-ICP47ΔR strain (P = 0.3962). Adoptive transfer of CD4+ cells did not significantly alter (P >0.05) survival of mice infected with either virus.

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References

    1. Früh K, Ahn K, Djaballah H, Sempe P, van Endert PM, Tampe R, Peterson PA, Yang Y. A viral inhibitor of peptide transporters for antigen presentation. Nature. 1995;375:415–418. - PubMed
    1. Hill A, Jugovic P, York I, Russ G, Bennink J, Yewdell J, Ploegh H, Johnson D. Herpes simplex virus turns off TAP to evade host immunity. Nature. 1995;375:411–415. - PubMed
    1. Ahn K, Meyer TH, Uebel S, Sempé P, Djaballah H, Yang Y, Peterson PA, Früh K, Tampé R. Molecular mechanism and species specificity of TAP inhibition by herpes simplex virus protein ICP47. EMBO (Euro Mol Biol Organ) J. 1996;15:3247–3255. - PMC - PubMed
    1. Tomazin R, Hill AB, Jugovic P, York I, van Endert P, Ploegh HL, Andrews DW, Johnson DC. Stable binding of the herpes simplex virus ICP47 protein to the peptide binding site of TAP. EMBO (Eur Mol Biol Organ) J. 1996;15:3256–3266. - PMC - PubMed
    1. Johnson, D.C., and A.B. Hill. 1998. Herpesviruses and immune evasion. Curr. Top. Microbiol. Immunol. In press. - PubMed

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