HUMAN T CELL RESPONSE TO HERPES SIMPLEX VIRUS ANTIGEN IN VITRO

ABSTRACT Cytolytic T cells play a major role in controlling herpes simplex virus type 2 (HSV-2) infections in humans. In an effort to more thoroughly evaluate the response to HSV-2 directly, ex vivo, we developed an enzyme-linked immunospot (ELISPOT) assay that utilized pools of overlapping synthetic peptides presented by autologous dendritic cells to purified CD8+ T cells. Donor response rates to individual open reading frames (ORFs) ranged from fewer than 5% responding to as many as 70% responding, with the greatest frequency of responses (by ORF) being directed against UL39, UL25, UL27, ICP0, UL46, and UL47 in descending order of frequency. HSV-2-seropositive subjects responded to as few as 3 or as many as 46 of the 48 ORFs tested, with a median of 11 ORFs recognized. HLA-B*07 expression correlated with stronger responses overall that were directed primarily against UL49 and UL46. Cumulative precursor frequencies in the blood ranged from 500 to almost 6,000 HSV-2 spot-forming units/106 CD8+ T cells. The magnitude and breadth of the response in the infected population were greater than previously appreciated. Whether this variability in the CD8+ T-cell response within individuals is associated with the frequency of viral reactivation warrants further study.

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The Cytotoxic T-Cell Response to Herpes Simplex Virus Type 1 Infection of C57BL/6 Mice Is Almost Entirely Directed against a Single Immunodominant Determinant

Journal of Virology ◽

10.1128/jvi.73.9.7619-7626.1999 ◽

1999 ◽

Vol 73 (9) ◽

pp. 7619-7626 ◽

Cited By ~ 116

Author(s):

Morgan E. Wallace ◽

Rachael Keating ◽

William R. Heath ◽

Francis R. Carbone

Keyword(s):

T Cells ◽

Herpes Simplex Virus ◽

Herpes Simplex ◽

T Cell ◽

Herpes Simplex Virus Type ◽

Cell Response ◽

T Cell Response ◽

Simplex Virus ◽

Hsv 1

ABSTRACT Many virus infections give rise to surprisingly limited T-cell responses directed to very few immunodominant determinants. We have been examining the cytotoxic T-lymphocyte (CTL) response to herpes simplex virus type 1 (HSV-1) infection. Previous studies have identified the glycoprotein B-derived peptide from residues 498 to 505 (gB498–505) as one of at least three determinants recognized by HSV-1-specific CTLs isolated from C57BL/6 mice. We had previously found that in vitro-derived CTLs directed to gB498–505 show a characteristic pattern of T-cell receptor (TCR) usage, with 60% of gB498–505-specific CD8+ T cells expressing BV10+ TCR β chains and a further 20% expressing BV8S1. In this report, we confirm that this TCR V-region bias is also reflected in the ex vivo response to HSV-1 infection. A high proportion of activated CD8+draining lymph node cells were found to express these dominant V regions, suggesting that a substantial number of in vivo responding T cells were directed to this one viral determinant. The use of an HSV-1 deletion mutant lacking the gB498–505 determinant in combination with accurate intracellular gamma interferon staining allowed us to quantify the extent of gB-specific T-cell dominance. Together, these results suggested that between 70 and 90% of all CD8+ HSV-1-specific T cells target gB498–505. While deletion of this determinant resulted in an attenuated CD8+ T-cell response, it also permitted the emergence of one or more previously unidentified cryptic specificities. Overall, HSV-1 infection of C57BL/6 mice results in an extremely focused pattern of CD8+ T-cell selection in terms of target specificity and TCR expression.

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CD4+ CD25+ T Cells Regulate Vaccine-Generated Primary and Memory CD8+ T-Cell Responses against Herpes Simplex Virus Type 1

Journal of Virology ◽

10.1128/jvi.78.23.13082-13089.2004 ◽

2004 ◽

Vol 78 (23) ◽

pp. 13082-13089 ◽

Cited By ~ 109

Author(s):

Felix N. Toka ◽

Susmit Suvas ◽

Barry T. Rouse

Keyword(s):

T Cells ◽

Herpes Simplex Virus ◽

Herpes Simplex ◽

T Cell ◽

Cell Response ◽

Cell Activity ◽

T Cell Response ◽

Cell Reactivity ◽

T Cell Reactivity ◽

Simplex Virus

ABSTRACT It has become evident that naturally occurring CD25+ regulatory T cells (Treg cells) not only influence self-antigen specific immune response but also dampen foreign antigen specific immunity. This report extends our previous findings by demonstrating that immunity to certain herpes simplex virus (HSV) vaccines is significantly elevated and more effective if Treg cell response is curtailed during either primary or recall immunization. The data presented here show that removal of CD25+ Treg cells prior to SSIEFARL-CpG or gB-DNA immunization significantly enhanced the resultant CD8+ T-cell response to the immunodominant SSIEFARL peptide. The enhanced CD8+ T-cell reactivity in Treg cell-depleted animals was between two- and threefold and evident in both acute and memory stages. Interestingly, removal of CD25+ Treg cells during the memory recall response to plasmid immunization resulted in a twofold increase in CD8+ T-cell memory pool. Moreover, in the challenge experiments, memory CD8+ T cells generated with plasmid DNA in the absence of Treg cells cleared the virus more effectively compared with control groups. We conclude that CD25+ Treg cells quantitatively as well as qualitatively affect the memory CD8+ T-cell response generated by gB-DNA vaccination against HSV. However, it remains to be seen if all types of vaccines against HSV are similarly affected by CD25+ Treg cells and if it is possible to devise means of limiting Treg cell activity to enhance vaccine efficacy.

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Erythema multiforme lesions are associated with expression of a herpes simplex virus (HSV) gene and qualitative alterations in the HSV-specific T-cell response

British Journal of Dermatology ◽

10.1046/j.1365-2133.1998.02260.x ◽

1998 ◽

Vol 138 (6) ◽

pp. 952-964 ◽

Cited By ~ 41

Author(s):

Kokuba ◽

Imafuku ◽

Huang ◽

Aurelian ◽

Burnett

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

T Cell ◽

Erythema Multiforme ◽

Cell Response ◽

T Cell Response ◽

Simplex Virus

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Induction of CD8 T-Cell-Specific Systemic and Mucosal Immunity against Herpes Simplex Virus with CpG-Peptide Complexes

Journal of Virology ◽

10.1128/jvi.76.13.6568-6576.2002 ◽

2002 ◽

Vol 76 (13) ◽

pp. 6568-6576 ◽

Cited By ~ 42

Author(s):

Malgorzata Gierynska ◽

Uday Kumaraguru ◽

Seong-Kug Eo ◽

Sujin Lee ◽

Arthur Krieg ◽

...

Keyword(s):

T Cells ◽

Herpes Simplex Virus ◽

Herpes Simplex ◽

T Cell ◽

Cell Response ◽

T Cell Response ◽

Specific Response ◽

Cpg Odn ◽

Adjuvant Activity ◽

Simplex Virus

ABSTRACT Oligodeoxynucleotides (ODN) containing unmethylated CpG motifs exert powerful adjuvant activity in vivo and in vitro. Administered with antigen they induce a population of antigen-specific CD8+ T cells. In this study we immunized C57BL/6 mice with bioactive CpG ODN combined with an immunodominant epitope derived from herpes simplex virus (HSV) glycoprotein B (amino acids 498 to 505; SSIEFARL) and analyzed the magnitude and durability of the peptide-specific response. The effectiveness of the CD8+ T-cell response as measured by peptide-specific tetramers, peptide-induced intracellular gamma interferon expression, and resistance to systemic and mucosal challenge during the acute and memory phases was compared with the response induced by immunization with recombinant vaccinia virus encoding SSIEFARL as a minigene (VvgB498-505). Confirming the reports of others, our results demonstrate that the CpG ODN-peptide approach generates an antigen-specific CD8+ T-cell population, but the frequency of CD8+ T cells is lower than that induced by VvgB498-505. Nevertheless, the protection level was comparable when mice were systemically and mucosally challenged during the acute phase. However, such responses by both groups waned with time and were functionally less effective. Still, our results indicate that the CpG ODN-peptide immunization system holds promise as a means of selectively inducing a CD8+ T-cell response against HSV.

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