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

Eriksson, Kristina; Bellner, Lars; Görander, Staffan; Löwhagen, Gun-Britt; Rydberg, Kristina; Liljeqvist, Jan‐Åke

doi:10.1099/vir.0.79978-0

Cited by 29 publications

(22 citation statements)

References 56 publications

(45 reference statements)

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“…1). We and others have previously reported that asymptomatic HSV-2 infection is associated with higher T-cell recall IFN-␥ responses, compared with symptomatic HSV-2 in- fection (10,37). However, we could not confirm this observation in the current patient cohort (data not shown).…”

Section: Genetic Variations In Stat4contrasting

confidence: 56%

“…However, the treatment of mice with IFN-␥ circumvents the need for CD4 ϩ T cells, which implies that the main function of CD4 ϩ T cells in HSV-2-specific immunity is to produce IFN-␥ (14). The situation is similar in humans, as HSV-2-infected individuals with recurrent disease have impaired virusspecific IFN-␥ responses compared with asymptomatic HSV-2 carriers (10,37).…”

mentioning

confidence: 73%

“…The clinical effects of HSV-2 infection range from no symptoms (asymptomatic infection) to severe and recurrent episodes of genital lesions and ulcers. Although the mechanisms underlying these different disease outcomes are not known, strong gamma interferon (IFN-␥) responses (10,37), previous HSV-1 infection (22), high levels of mannan-binding lectin (13), specific HLA alleles (23), and variants of both the TLR2 gene (6) and the gene encoding mannose-binding lectin 2 (34) increase the likelihood of an asymptomatic infection.…”

mentioning

confidence: 99%

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STAT4 Regulates Antiviral Gamma Interferon Responses and Recurrent Disease during Herpes Simplex Virus 2 Infection

Svensson

Nordström

Shestakov

et al. 2012

J Virol

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STAT4 is an important transcription factor that contributes to the incidence and severity of different autoimmune diseases and is implicated in the antiviral immune responses in mice. In this study, we evaluated the role of STAT4 in human and murine herpes simplex virus 2 (HSV-2) infections. We show that STAT4 regulates antiviral gamma interferon (IFN-␥) responses and disease severity during chronic HSV-2 infections in humans and vaccine-induced IFN-␥-mediated protection against HSV-2 infection in mice. In a cohort of 228 HSV-2-infected individuals, representing both patients with recurrent disease and asymptomatic HSV-2 carriers, we found that genetic variations in the STAT4 gene were associated with asymptomatic HSV-2 infection, as well as with increased in vitro secretion of IFN-␥ in response to the virus. Mice that lacked STAT4 had impaired HSV-2-specific IFN-␥ production and delayed-type hypersensitivity responses following vaccination, which led to impaired viral clearance in the genital tract of vaccinated animals after a genital HSV-2 challenge. We conclude that STAT4 plays an important role in IFN-␥-mediated HSV-2-specific immunity, affecting the severity of genital HSV-2 infection.

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Section: Genetic Variations In Stat4contrasting

confidence: 56%

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confidence: 73%

mentioning

confidence: 99%

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STAT4 Regulates Antiviral Gamma Interferon Responses and Recurrent Disease during Herpes Simplex Virus 2 Infection

Svensson

Nordström

Shestakov

et al. 2012

J Virol

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“…This immune escape might be of importance for the pathogenesis of HSV-2, in particular for the establishment of HSV-2 infection in individuals that are already infected with HSV-1. The acquired immune responses to HSV-1 and HSV-2 are, with the exception of the immune response to the gG-2 protein, highly cross-reactive (43)(44)(45)(46)). Yet, HSV-2 manages to infect HSV-1-seropositive individuals as efficiently as it infects individuals with no prior HSV exposure (47), perhaps as a consequence of a gG-2-induced ROS-mediated suppression of specific lymphocyte subsets.…”

Section: Discussionmentioning

confidence: 99%

A Proinflammatory Peptide from Herpes Simplex Virus Type 2 Glycoprotein G Affects Neutrophil, Monocyte, and NK Cell Functions

Bellner

Thorén²,

Nygren

et al. 2005

The Journal of Immunology

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We have identified a synthetic peptide derived from the secreted portion of HSV type 2 glycoprotein G, denoted gG-2p20, which has proinflammatory properties in vitro. The gG-2p20 peptide, corresponding to aa 190–205 of glycoprotein G-2, was a chemoattractant for both monocytes and neutrophils in a dose-dependent fashion, and also induced the release of reactive oxygen from these cells. The receptor mediating the responses was identified as the formyl peptide receptor. The gG-2p20-induced activation of phagocytes had a profound impact on NK cell functions. The reactive oxygen species produced by gG-2p20-activated phagocytes both inhibited NK cell cytotoxicity and accelerated the apoptotic cell death in NK cell-enriched lymphocyte populations. Hence, we have for the first time been able to identify a potential function of the secreted portion of HSV-2 glycoprotein G. We propose that the proinflammatory gG-2p20 peptide identified could contribute to a reduced function and viability of NK cells during HSV-2 infection due to its ability to recruit and activate phagocytic cells.

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“…Culture medium was changed, and cells were cultured for the indicated time before next assay. UV-inactivated virus was obtained by exposure of HSV-2 to UV irradiation for 15 min, as described previously (29). To separate virus particles from the cytokines secreted by Vero cells, virus stocks were added to 100-kDa centrifugal filter unit (Millipore) and centrifuged for 30 min at 1000 3 g. Membrane-retained HSV-2 was diluted and used to infect ME-180 cells.…”

Section: Hsv-2 Infectionmentioning

confidence: 99%

Herpes Simplex Virus Type 2 Infection of Human Epithelial Cells Induces CXCL9 Expression and CD4+ T Cell Migration via Activation of p38-CCAAT/Enhancer-Binding Protein-β Pathway

Huang

Luo

et al. 2012

The Journal of Immunology

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Recruitment of CD4+ T cells to infection areas after HSV-2 infection may be one of the mechanisms that account for increased HIV-1 sexual transmission. Lymphocytes recruited by chemokine CXCL9 are known to be important in control of HSV-2 infection in mice, although the underlying mechanism remains to be addressed. Based on our observation that CXCL9 expression is augmented in the cervical mucus of HSV-2–positive women, in this study we demonstrate that HSV-2 infection directly induces CXCL9 expression in primary cervical epithelial cells and cell lines, the principal targets of HSV-2, at both mRNA and protein levels. Further studies reveal that the induction of CXCL9 expression by HSV-2 is dependent upon a binding site for C/EBP-β within CXCL9 promoter sequence. Furthermore, CXCL9 expression is promoted at the transcriptional level through phosphorylating C/EBP-β via p38 MAPK pathway, leading to binding of C/EBP-β to the CXCL9 promoter. Chemotaxis assays indicate that upregulation of CXCL9 expression at the protein level by HSV-2 infection enhances the migration of PBLs and CD4+ T cells, whereas neutralization of CXCL9 or inhibition of p38-C/EBP-β pathway can significantly decrease the migration. Our data together demonstrate that HSV-2 induces CXCL9 expression in human cervical epithelial cells by activation of p38-C/EBP-β pathway through promoting the binding of C/EBP-β to CXCL9 promoter, which may recruit activated CD4+ T cells to mucosal HSV-2 infection sites and potentially increase the risk of HIV-1 sexual transmission.

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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

Cited by 29 publications

References 56 publications

STAT4 Regulates Antiviral Gamma Interferon Responses and Recurrent Disease during Herpes Simplex Virus 2 Infection

STAT4 Regulates Antiviral Gamma Interferon Responses and Recurrent Disease during Herpes Simplex Virus 2 Infection

A Proinflammatory Peptide from Herpes Simplex Virus Type 2 Glycoprotein G Affects Neutrophil, Monocyte, and NK Cell Functions

Herpes Simplex Virus Type 2 Infection of Human Epithelial Cells Induces CXCL9 Expression and CD4+ T Cell Migration via Activation of p38-CCAAT/Enhancer-Binding Protein-β Pathway

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