Diversity of the CD8+ T-Cell Response to Herpes Simplex Virus Type 2 Proteins among Persons with Genital Herpes

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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Differential roles of B cells and IFN-γ-secreting CD4+ T cells in innate and adaptive immune control of genital herpes simplex virus type 2 infection in mice

Journal of General Virology ◽

10.1099/0022-1317-82-4-845 ◽

2001 ◽

Vol 82 (4) ◽

pp. 845-853 ◽

Cited By ~ 98

Author(s):

Ali M. Harandi ◽

Bo Svennerholm ◽

Jan Holmgren ◽

Kristina Eriksson

Keyword(s):

T Cells ◽

Herpes Simplex Virus ◽

Herpes Simplex ◽

T Cell ◽

B Cells ◽

Virus Type ◽

Herpes Simplex Virus Type ◽

Ifn Γ ◽

Simplex Virus

The role of B, CD4+ T and CD8+ T cells in both primary genital infection with attenuated herpes simplex virus type 2 (HSV-2) and development of protective immunity to a later challenge with virulent HSV-2 using lymphocyte-deficient mice has been elucidated. Following primary inoculation with attenuated thymidine kinase-deficient (TK−) HSV-2, B cell-deficient (μMT) mice developed a local viraemia and transient genital inflammation, suggesting a role for B cells in the innate control of local infection and inflammation. Natural antibodies are implicated in this process, as passive transfer of normal serum into μMT mice significantly reduced HSV-2 TK− shedding in the vaginal lumen, although it did not affect subsequent inflammation. Protection against lethal HSV-2 challenge was noted in HSV-2-vaccinated wild-type, CD8+ T cell-deficient and μMT mice and was characterized by strong virus-specific IFN-γ responses in vitro and delayed type hypersensitivity (DTH) responses in vivo. In contrast, CD4+ T cell-deficient (CD4−/−) mice had impaired HSV-2-specific IFN-γ production and DTH responses and succumbed rapidly to genital HSV-2 challenge. However, protective responses to HSV-2 could be induced in HSV-2-vaccinated CD4−/− mice by treatment with recombinant IFN-γ. Taken together, these results suggest that CD4+ T cells secreting IFN-γ are critical for immune protection against lethal genital HSV-2 re-infection, whereas B cells/natural antibodies have anti-viral and -inflammatory effects in the innate control of a primary infection.

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Characterization of T-cell reactive epitopes in glycoprotein G of herpes simplex virus type 2 using synthetic peptides

Archives of Virology ◽

10.1007/s00705-005-0497-x ◽

2005 ◽

Vol 150 (7) ◽

pp. 1393-1406 ◽

Cited By ~ 2

Author(s):

L. Bellner ◽

G.-B. Löwhagen ◽

P. Tunbäck ◽

I. Nordström ◽

J.-Å. Liljeqvist ◽

...

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

T Cell ◽

Virus Type ◽

Herpes Simplex Virus Type ◽

Synthetic Peptides ◽

Glycoprotein G ◽

Simplex Virus

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CD4+ T-cell responses to herpes simplex virus type 2 (HSV-2) glycoprotein G are type specific and differ in symptomatic and asymptomatic HSV-2-infected individuals

Journal of General Virology ◽

10.1099/vir.0.79978-0 ◽

2004 ◽

Vol 85 (8) ◽

pp. 2139-2147 ◽

Cited By ~ 25

Author(s):

Kristina Eriksson ◽

Lars Bellner ◽

Staffan Görander ◽

Gun-Britt Löwhagen ◽

Petra Tunbäck ◽

...

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

T Cell ◽

Virus Type ◽

Herpes Simplex Virus Type ◽

Mononuclear Cells ◽

Glycoprotein G ◽

Simplex Virus ◽

Hsv 1

T-cell recognition of the secreted and membrane-bound portions of the herpes simplex virus type 2 (HSV-2) glycoprotein G (sgG-2 and mgG-2, respectively) was compared in symptomatic and asymptomatic HSV-2-infected individuals and in HSV-2-seronegative controls and the responses with HSV-1 glycoproteins C and E (gC-1 and gE-1) were compared. CD4+ T cells from HSV-2-infected individuals specifically recognized both sgG-2 and mgG-2, whereas HSV-1-infected and HSV-seronegative controls did not respond to these glycoproteins. The responses to gC-1 and gE-1, on the other hand, were not type specific, as blood mononuclear cells from both HSV-1- and HSV-2-infected individuals responded in vitro. There was an association between the status of the infection (symptomatic versus asymptomatic) and the CD4+ T-cell responsiveness. Symptomatic HSV-2-seropositive individuals responded with significantly lower Th1 cytokine production to sgG-2 and mgG-2 than did asymptomatic HSV-2-infected carriers, especially within the HSV-1-negative cohort. No differences in T-cell proliferation were observed between asymptomatic and symptomatic individuals. The results have implications for studies of HSV-2-specific CD4+ T-cell reactivity in general and for analysis of immunological differences between asymptomatic and symptomatic individuals in particular.

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Caspase 9 Is Essential for Herpes Simplex Virus Type 2-Induced Apoptosis in T Cells

Journal of Virology ◽

10.1128/jvi.01726-09 ◽

2010 ◽

Vol 84 (6) ◽

pp. 3116-3120 ◽

Cited By ~ 20

Author(s):

Michael J. Vanden Oever ◽

Jin-Young Han

Keyword(s):

T Cells ◽

Herpes Simplex Virus ◽

Herpes Simplex ◽

Virus Type ◽

Herpes Simplex Virus Type ◽

Intrinsic Pathway ◽

Caspase 9 ◽

Induced Apoptosis ◽

Simplex Virus

ABSTRACT Herpes simplex virus type 2 (HSV-2) induces apoptosis in T cells by a caspase-dependent mechanism. Apoptosis can occur via extrinsic (death receptor) and/or intrinsic (mitochondrial) pathways. Here, we show that the initiator caspase for the intrinsic pathway is activated in T cells following HSV-2 exposure. To determine the respective contributions of intrinsic and extrinsic pathways, we assessed apoptosis in Jurkat cells that are deficient in caspase 8 or Fas-associating protein with death domain (FADD) for the extrinsic pathway and in cells deficient in caspase 9 for the intrinsic pathway. Our results indicate HSV-2-induced apoptosis in T cells occurs via the intrinsic pathway.

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BiTEs Expressed by an Oncolytic Herpes Simplex Virus Type 2 Can Transform Heterologous T Cells Into Uniform Tumor Killer Cells

SSRN Electronic Journal ◽

10.2139/ssrn.3941808 ◽

2021 ◽

Author(s):

Jing Jin ◽

Runyang Wang ◽

Junhan Yang ◽

Han Hu ◽

Di Wang ◽

...

Keyword(s):

T Cells ◽

Herpes Simplex Virus ◽

Herpes Simplex ◽

Virus Type ◽

Herpes Simplex Virus Type ◽

Killer Cells ◽

Oncolytic Herpes Simplex Virus ◽

Simplex Virus

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CD4+ T Cells Are Required for the Priming of CD8+ T Cells following Infection with Herpes Simplex Virus Type 1

Journal of Virology ◽

10.1128/jvi.01997-08 ◽

2009 ◽

Vol 83 (10) ◽

pp. 5256-5268 ◽

Cited By ~ 32

Author(s):

Naveen K. Rajasagi ◽

Sadik H. Kassim ◽

Christina M. Kollias ◽

Xiangyi Zhao ◽

Robert Chervenak ◽

...

Keyword(s):

T Cells ◽

Herpes Simplex Virus ◽

Herpes Simplex ◽

T Cell ◽

Herpes Simplex Virus Type ◽

T Cell Response ◽

Simplex Virus ◽

T Cell Help ◽

Hsv 1

ABSTRACT The role of CD4+ helper T cells in modulating the acquired immune response to herpes simplex virus type 1 (HSV-1) remains ill defined; in particular, it is unclear whether CD4+ T cells are needed for the generation of the protective HSV-1-specific CD8+-T-cell response. This study examined the contribution of CD4+ T cells in the generation of the primary CD8+-T-cell responses following acute infection with HSV-1. The results demonstrate that the CD8+-T-cell response generated in the draining lymph nodes of CD4+-T-cell-depleted C57BL/6 mice and B6-MHC-II−/− mice is quantitatively and qualitatively distinct from the CD8+ T cells generated in normal C57BL/6 mice. Phenotypic analyses show that virus-specific CD8+ T cells express comparable levels of the activation marker CD44 in mice lacking CD4+ T cells and normal mice. In contrast, CD8+ T cells generated in the absence of CD4+ T cells express the interleukin 2 receptor α-chain (CD25) at lower levels. Importantly, the CD8+ T cells in the CD4+-T-cell-deficient environment are functionally active with respect to the expression of cytolytic activity in vivo but exhibit a diminished capacity to produce gamma interferon and tumor necrosis factor alpha. Furthermore, the primary expansion of HSV-1-specific CD8+ T cells is diminished in the absence of CD4+-T-cell help. These results suggest that CD4+-T-cell help is essential for the generation of fully functional CD8+ T cells during the primary response to HSV-1 infection.

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