scholarly journals B7 Costimulation Molecules Expressed from the Herpes Simplex Virus 2 Genome Rescue Immune Induction in B7-Deficient Mice

2007 ◽  
Vol 81 (22) ◽  
pp. 12200-12209 ◽  
Author(s):  
Lydia G. Thebeau ◽  
Sri P. Vagvala ◽  
Yee M. Wong ◽  
Lynda A. Morrison
Keyword(s):  
T Cells ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Immune Responses ◽  
T Cell Activation ◽  
Cell Activation ◽  
Challenge Virus ◽  
Simplex Virus ◽  
Herpes Simplex Virus 2

ABSTRACT The interaction between B7 costimulation molecules on antigen-presenting cells and CD28 on antigen-responsive T cells is essential for T-cell activation and maturation of immune responses to herpes simplex virus (HSV) infection. Vaccine-induced immune responses also depend upon adequate upregulation of B7 costimulation molecules, but this signal may be limiting for replication-defective virus vaccines. We investigated whether expression of B7 costimulation molecules by a prototypical replication-defective antiviral vaccine could enhance immune responses to the vaccine and whether B7-1 and B7-2 would be similarly effective. We altered an ICP8− replication-defective strain of HSV type 2 (HSV-2), 5BlacZ, to encode either murine B7-1 or B7-2. B7 molecule expression was detected on the surface of cells infected in vitro and at the RNA level in tissue of immunized mice. Immunization of B7-1/B7-2 knockout mice with B7-encoding virus modestly expanded the number of gamma interferon-producing T cells and significantly augmented class-switched HSV-specific antibody responses compared with the parental virus. Mice immunized with either B7-expressing virus showed less replication of challenge virus in the genital mucosa than mice immunized with 5BlacZ, markedly fewer signs of genital and neurological disease, and little weight loss. Virtually all mice immunized with B7-encoding virus survived challenge with a large dose of HSV-2, whereas most 5BlacZ-immunized mice succumbed to infection. These results indicate that protective immune responses can be enhanced by the inclusion of host B7 costimulation molecules in a prototypical replication-defective HSV vaccine against HSV-2 genital infection and that B7-1 and B7-2 induce immune responses with similar capacities to fight HSV-2 infection.

scholarly journals Short Communication: T Cell Activation in HIV-1/Herpes Simplex Virus-2-Coinfected Kenyan Women Receiving Valacyclovir

2013 ◽  
Vol 29 (1) ◽  
pp. 94-98 ◽  
Author(s):  
Alison C. Roxby ◽  
Amy Y. Liu ◽  
Alison L. Drake ◽  
James N. Kiarie ◽  
Barbra Richardson ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Short Communication ◽  
Kenyan Women ◽  
Simplex Virus ◽  
Herpes Simplex Virus 2 ◽  
Hiv 1

scholarly journals Dendritic Cell Autophagy Contributes to Herpes Simplex Virus-Driven Stromal Keratitis and Immunopathology

mBio ◽  
2015 ◽  
Vol 6 (6) ◽  
Author(s):  
Yike Jiang ◽  
Xiaotang Yin ◽  
Patrick M. Stuart ◽  
David A. Leib
Keyword(s):  
T Cells ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
T Cell ◽  
Dendritic Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Herpetic Stromal Keratitis ◽  
Stromal Keratitis ◽  
Simplex Virus

ABSTRACTHerpetic stromal keratitis (HSK) is a blinding ocular disease that is initiated by HSV-1 and characterized by chronic inflammation in the cornea. Although HSK immunopathology of the cornea is well documented in animal models, events preceding this abnormal inflammatory cascade are poorly understood. In this study, we have examined the activation of pathological CD4+T cells in the development of HSK. Dendritic cell autophagy (DC-autophagy) is an important pathway regulating major histocompatibility complex class II (MHCII)-dependent antigen presentation and proper CD4+T cell activation during infectious diseases. Using DC-autophagy-deficient mice, we found that DC-autophagy significantly and specifically contributes to HSK disease without impacting early innate immune infiltration, viral clearance, or host survival. Instead, the observed phenotype was attributable to the abrogated activation of CD4+T cells and reduced inflammation in HSK lesions. We conclude that DC-autophagy is an important contributor to primary HSK immunopathology upstream of CD4+T cell activation.IMPORTANCEHerpetic stromal keratitis (HSK) is the leading cause of infectious blindness in the United States and a rising cause worldwide. HSK is induced by herpes simplex virus 1 but is considered a disease of inappropriately sustained inflammation driven by CD4+T cells. In this study, we investigated whether pathways preceding CD4+T cell activation affect disease outcome. We found that autophagy in dendritic cells significantly contributed to the incidence of HSK. Dendritic cell autophagy did not alter immune control of the virus or neurological disease but specifically augmented CD4+T cell activation and pathological corneal inflammation. This study broadens our understanding of the immunopathology that drives HSK and implicates the autophagy pathway as a new target for therapeutic intervention against this incurable form of infectious blindness.

A Homogenous 384-Well High Throughput Screen for Novel Tumor Necrosis Factor Receptor: Ligand Interactions Using Time Resolved Energy Transfer

1999 ◽  
Vol 4 (4) ◽  
pp. 205-214 ◽  
Author(s):  
K. J. Moore ◽  
S. Turconi ◽  
A. Miles-Williams ◽  
H. Djaballah ◽  
P. Hurskainen ◽  
...  
Keyword(s):  
Energy Transfer ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Virus Type ◽  
T Cell Activation ◽  
Herpes Simplex Virus Type ◽  
Cell Activation ◽  
Time Resolved ◽  
Well Assay ◽  
Simplex Virus

The herpes virus entry mediator (HVEM) receptor and its ligand, HVEM-L, are involved in both herpes simplex virus type-1 (HSV-1) herpes simplex virus type-2 (HSV-2) infection, and in T-cell activation such that antagonists of this interaction are expected to have utility in viral and inflammatory diseases. In this report we describe the configuration of a homogeneous 384-well assay based on time-resolved energy transfer from a europium chelate on the HVEM receptor to an allophycocyanin (APC) acceptor on the ligand. Specific time resolved emission from the acceptor is observed on receptor:ligand complex formation. The results of various direct and indirect labeling strategies are described. Several assay optimization experiments were necessary to obtain an assay that was robust to automation and file compound interference while sensitive to the effect of potential inhibitors. The signal was stable for more than 24 h at room temperature using the Eu3+ chelates, suggesting no dissociation of the lanthanide ion. The 384-well assay was readily automated and was able to identify more than 99.5% of known positive controls in the validation studies successfully. Screening identified both a series of known potent inhibitors and several structural classes of hits that readily deconvoluted to yield single compound inhibitors with the desired functional activity in secondary biological assays. The equivalence of the data in 384- and 1536-well formats indicates that routine implementation of 1536-well chelate-based energy transfer screening appears to be primarily limited by liquid handling rather than detection issues.

scholarly journals US6 Gene Deletion in Herpes Simplex Virus Type 2 Enhances Dendritic Cell Function and T Cell Activation

2017 ◽  
Vol 8 ◽  
Author(s):  
Angello Retamal-Díaz ◽  
Kayla A. Weiss ◽  
Eduardo I. Tognarelli ◽  
Mariela Freire ◽  
Susan M. Bueno ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Dendritic Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Gene Deletion ◽  
Cell Function ◽  
Dendritic Cell Function ◽  
Simplex Virus

scholarly journals Zinc Acetate/Carrageenan Gels Exhibit Potent ActivityIn Vivoagainst High-Dose Herpes Simplex Virus 2 Vaginal and Rectal Challenge

2011 ◽  
Vol 56 (1) ◽  
pp. 358-368 ◽  
Author(s):  
José A. Fernández-Romero ◽  
Ciby J. Abraham ◽  
Aixa Rodriguez ◽  
Larisa Kizima ◽  
Ninochka Jean-Pierre ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Zinc Acetate ◽  
Sexual Transmission ◽  
High Dose ◽  
Acetate Solution ◽  
Sexual Transmission Of Hiv ◽  
Simplex Virus ◽  
Herpes Simplex Virus 2

ABSTRACTTopical microbicides that block the sexual transmission of HIV and herpes simplex virus 2 (HSV-2) are desperately needed to reduce the incidence of HIV infections worldwide. Previously we completed phase 3 testing of the carrageenan-based gel Carraguard. Although the trial did not show that Carraguard is effective in preventing HIV transmission during vaginal sex, it did show that Carraguard is safe when used weekly for up to 2 years. Moreover, Carraguard hasin vitroactivity against human papillomavirus (HPV) and HSV-2 and favorable physical and rheological properties, which makes it a useful vehicle to deliver antiviral agents such as zinc acetate. To that end, we previously reported that a prototype zinc acetate carrageenan gel protects macaques against vaginal challenge with combined simian-human immunodeficiency virus reverse transcriptase (SHIV-RT). Herein, we report the safety and efficacy of a series of zinc acetate and/or carrageenan gels. The gels protected mice (75 to 85% survival;P< 0.001) against high-dose (106-PFU) HSV-2 vaginal or rectal challenge. In contrast, zinc acetate formulated in HEC (hydroxyethylcellulose; or the Universal Placebo) failed to protect mice against the high-dose vaginal HSV-2 challenge (similar to aqueous zinc acetate solution and the placebo controls). The gels were found to be effective spreading gels, exhibited limited toxicityin vitro, caused minimal damage to the architecture of the cervicovaginal and rectal mucosaein vivo, and induced no increased susceptibility to HSV-2 infection in a mouse model. Our results provide a strong rationale to further optimize and evaluate the zinc acetate/carrageenan gels for their ability to block the sexual transmission of HIV and HSV-2.

scholarly journals Herpes Simplex Virus γ34.5 Interferes with Autophagosome Maturation and Antigen Presentation in Dendritic Cells

mBio ◽  
2012 ◽  
Vol 3 (5) ◽  
Author(s):  
Philipe A. M. Gobeil ◽  
David A. Leib
Keyword(s):  
Dendritic Cells ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Host Immunity ◽  
Herpes Simplex Virus 1 ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACTThe cellular autophagy response induced by herpes simplex virus 1 (HSV-1) is countered by the viral γ34.5 protein. γ34.5 modulates autophagy by binding to the host autophagy protein Beclin-1 and through this binding inhibits the formation of autophagosomes in fibroblasts and neurons. In contrast, in this study dendritic cells (DCs) infected with HSV-1 showed an accumulation of autophagosomes and of the long-lived protein p62. No such accumulations were observed in DCs infected with a γ34.5-null virus or a virus lacking the Beclin-binding domain (BBD) of γ34.5. To explore this further, we established stably transduced DC lines to show that γ34.5 expression alone induced autophagosome accumulation yet prevented p62 degradation. In contrast, DCs expressing a BBD-deleted mutant of γ34.5 were unable to modulate autophagy. DCs expressing γ34.5 were less capable of stimulating T-cell activation and proliferation in response to intracellular antigens, demonstrating an immunological consequence of inhibiting autophagy. Taken together, these data show that in DCs, γ34.5 antagonizes the maturation of autophagosomes and T cell activation in a BBD-dependent manner, illustrating a unique interface between HSV and autophagy in antigen-presenting cells.IMPORTANCEHerpes simplex virus 1 (HSV-1) is a highly prevalent pathogen causing widespread morbidity and some mortality. HSV infections are lifelong, and there are no vaccines or antivirals to cure HSV infections. The ability of HSV to modulate host immunity is critical for its virulence. HSV inhibits host autophagy, a pathway with importance in many areas of health and disease. Autophagy is triggered by many microbes, some of which harness autophagy for replication; others evade autophagy or prevent it from occurring. Autophagy is critical for host defense, either by directly degrading the invading pathogen (“xenophagy”) or by facilitating antigen presentation to T cells. In this study, we show that HSV manipulates autophagy through an unsuspected mechanism with a functional consequence of reducing T cell stimulation. These data further our understanding of how HSV evades host immunity to persist for the lifetime of its host, facilitating its spread in the human population.

scholarly journals Topical Herpes Simplex Virus 2 (HSV-2) Vaccination with Human Papillomavirus Vectors Expressing gB/gD Ectodomains Induces Genital-Tissue-Resident Memory CD8+T Cells and Reduces Genital Disease and Viral Shedding after HSV-2 Challenge

2014 ◽  
Vol 89 (1) ◽  
pp. 83-96 ◽  
Author(s):  
Nicolas Çuburu ◽  
Kening Wang ◽  
Kyle N. Goodman ◽  
Yuk Ying Pang ◽  
Cynthia D. Thompson ◽  
...  
Keyword(s):  
T Cells ◽  
Human Papillomavirus ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Neutralizing Antibodies ◽  
Viral Shedding ◽  
Monophosphoryl Lipid A ◽  
Simplex Virus ◽  
Herpes Simplex Virus 2 ◽  
Genital Tissue

ABSTRACTNo herpes simplex virus 2 (HSV-2) vaccine has been licensed for use in humans. HSV-2 glycoproteins B (gB) and D (gD) are targets of neutralizing antibodies and T cells, but clinical trials involving intramuscular (i.m.) injection of HSV-2 gB and gD in adjuvants have not been effective. Here we evaluated intravaginal (ivag) genetic immunization of C57BL/6 mice with a replication-defective human papillomavirus pseudovirus (HPV PsV) expressing HSV-2 gB (HPV-gB) or gD (HPV-gD) constructs to target different subcellular compartments. HPV PsV expressing a secreted ectodomain of gB (gBsec) or gD (gDsec), but not PsV expressing a cytoplasmic or membrane-bound form, induced circulating and intravaginal-tissue-resident memory CD8+T cells that were able to secrete gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α) as well as moderate levels of serum HSV neutralizing antibodies. Combined immunization with HPV-gBsec and HPV-gDsec (HPV-gBsec/gDsec) vaccines conferred longer survival after vaginal challenge with HSV-2 than immunization with HPV-gBsec or HPV-gDsec alone. HPV-gBsec/gDsec ivag vaccination was associated with a reduced severity of genital lesions and lower levels of viral shedding in the genital tract after HSV-2 challenge. In contrast, intramuscular vaccination with a soluble truncated gD protein (gD2t) in alum and monophosphoryl lipid A (MPL) elicited high neutralizing antibody titers and improved survival but did not reduce genital lesions and viral shedding. Vaccination combining ivag HPV-gBsec/gDsec and i.m. gD2t-alum-MPL improved survival and reduced genital lesions and viral shedding. Finally, high levels of circulating HSV-2-specific CD8+T cells, but not serum antibodies, correlated with reduced viral shedding. Taken together, our data underscore the potential of HPV PsV as a platform for a topical mucosal vaccine to control local manifestations of primary HSV-2 infection.IMPORTANCEGenital herpes is a highly prevalent chronic disease caused by HSV infection. To date, there is no licensed vaccine against HSV infection. This study describes intravaginal vaccination with a nonreplicating HPV-based vector expressing HSV glycoprotein antigens. The data presented in this study underscore the potential of HPV-based vectors as a platform for the induction of genital-tissue-resident memory T cell responses and the control of local manifestations of primary HSV infection.

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