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. 2003 Feb;77(4):2445-51.
doi: 10.1128/jvi.77.4.2445-2451.2003.

The early expression of glycoprotein B from herpes simplex virus can be detected by antigen-specific CD8+ T cells

Scott N Mueller  1 , Claerwen M Jones, Weisan Chen, Yoshihiro Kawaoka, Maria R Castrucci, William R Heath, Francis R Carbone
Affiliations

The early expression of glycoprotein B from herpes simplex virus can be detected by antigen-specific CD8+ T cells

Scott N Mueller et al. J Virol. 2003 Feb.

Abstract

The immune response to cutaneous herpes simplex virus type 1 (HSV-1) infection begins with remarkable rapidity. Activation of specific cytotoxic T lymphocytes (CTL) begins within hours of infection, even though the response within the draining lymph nodes peaks nearly 5 days later. HSV gene products are classified into three main groups, alpha, beta, and gamma, based on their kinetics and requirements for expression. In C57BL/6 mice, the immunodominant epitope from HSV is derived from glycoprotein B (gB(498-505)). While gB is considered a gamma or "late" gene product, previous reports have indicated that some level of gene expression may occur soon after infection. Using brefeldin A as a specific inhibitor of viral antigen presentation to major histocompatibility complex class I-restricted CTL, we have formally addressed the timing of gB peptide expression in an immunologically relevant manner following infection. Presentation of gB peptide detected by T-cell activation was first observed within 2 h of infection. Comparison with another viral epitope expressed early during infection, HSV-1 ribonucleotide reductase, demonstrated that gB is presented with the same kinetics as this classical early-gene product. Moreover, this rapidity of gB expression was further illustrated via rapid priming of naïve transgenic CD8(+) T cells in vivo after HSV-1 infection of mice. These results establish that gB is expressed rapidly following HSV-1 infection, at levels capable of effectively stimulating CD8(+) T cells.

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Figures

FIG. 1.
FIG. 1.
HSV-1 gB498-505 is expressed and presented to CD8+ T cells within 2 h of infection in vitro. CD8+ T cells from gBT-I mice were cultured with HSV-1 infected PMEFs, and BFA was added at intervals. The cells were then stained with anti-CD8-APC and anti-IFN-γ-phycoerythrin antibodies for FACS analysis. Numbers in the top left of each plot represent BFA addition time (in minutes); NA, no-virus control. Numbers in the top right within the gated regions represent the percentage of IFN-γ+ CD8+ T cells. Results of one representative experiment of six are shown.
FIG. 2.
FIG. 2.
Professional and nonprofessional APCs present gB498-505 with the same kinetics after infection with HSV-1. (A) The assay was performed as described in the legend to Fig. 1, with either spleen-derived DCs or PMEFs as APCs in combination with gBT T cells. (B) To determine the maximal possible levels of IFN-γ production by the readout gBT-I T cells, PMEFs were pulsed with serial dilutions of gB498-505 peptide and BFA was added after 2 h of culture. CD8+ T cells were subjected to FACS analysis for IFN-γ production. Results of one representative experiment of three are shown.
FIG. 3.
FIG. 3.
gB is presented with the kinetics of an early-gene product. PMEFs were infected with HSV-1 KOS or either of the recombinant viruses WSN/NA/gB or WSN/NA/OVA and incubated with gBT-specific, gB-specific (gB498-505), NP-specific (NP366-374) or RR-specific (RR822-829) T cells prior to addition of BFA at increasing intervals. IFN-γ production was determined by flow cytometric analysis of gated CD8+ T cells. NA, no virus. Results of one representative experiment of four are shown.
FIG. 4.
FIG. 4.
De novo synthesis of viral proteins is required for in vitro antigen presentation. These experiments were set up as described in the legend to Fig. 1; however, PMEFs were infected with either HSV-1 or UV-inactivated HSV-1 (A) or the recombinant HSV-1 strains KΔ318 or KΔ5C (B). BFA was added to the cultures at various intervals following infection, before flow cytometric analysis of CD8+ T cells for IFN-γ production. NA, no virus. Results reflect three independent experiments.
FIG. 5.
FIG. 5.
Rapid priming of naive T cells in vivo closely mirrors in vitro antigen presentation kinetics. Mice adoptively transferred with naive gBT-I T cells were sacrificed after intravenous immunization with gB498-505 peptide (i), HSV-1 KOS (ii), or either of KΔ318, KΔ5C, or UV-inactivated KOS (iii), and CD8+ T cells were analyzed for the expression of CD69 at 15 to 60 min (i), 1 to 4 h (ii), or 6 h (iii) after immunization. Similar results were obtained in three additional experiments.
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