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

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.

Download Full-text

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

mBio ◽

10.1128/mbio.01426-15 ◽

2015 ◽

Vol 6 (6) ◽

Cited By ~ 26

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.

Download Full-text

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

Journal of Virology ◽

10.1128/jvi.01224-07 ◽

2007 ◽

Vol 81 (22) ◽

pp. 12200-12209 ◽

Cited By ~ 7

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.

Download Full-text

Modulation of microglia and CD8+ T cell activation during the development of stress-induced herpes simplex virus type-1 encephalitis

Brain Behavior and Immunity ◽

10.1016/j.bbi.2007.01.005 ◽

2007 ◽

Vol 21 (6) ◽

pp. 791-806 ◽

Cited By ~ 33

Author(s):

Aji Nair ◽

John Hunzeker ◽

Robert H. Bonneau

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

T Cell ◽

Virus Type ◽

T Cell Activation ◽

Herpes Simplex Virus Type ◽

Cell Activation ◽

Cd8 T Cell ◽

Simplex Virus

Download Full-text

An Adjuvanted Herpes Simplex Virus 2 Subunit Vaccine Elicits a T Cell Response in Mice and Is an Effective Therapeutic Vaccine in Guinea Pigs

Journal of Virology ◽

10.1128/jvi.02745-12 ◽

2013 ◽

Vol 87 (7) ◽

pp. 3930-3942 ◽

Cited By ~ 62

Author(s):

M. Skoberne ◽

R. Cardin ◽

A. Lee ◽

A. Kazimirova ◽

V. Zielinski ◽

...

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

T Cell ◽

Cell Response ◽

Guinea Pigs ◽

Subunit Vaccine ◽

Therapeutic Vaccine ◽

T Cell Response ◽

Simplex Virus ◽

Herpes Simplex Virus 2

Download Full-text

Histidine-Rich Glycoprotein Inhibits HIV-1 Infection in a pH-Dependent Manner

Journal of Virology ◽

10.1128/jvi.01749-18 ◽

2018 ◽

Vol 93 (4) ◽

Cited By ~ 2

Author(s):

Ezequiel Dantas ◽

Fernando Erra Díaz ◽

Pehuén Pereyra Gerber ◽

Augusto Varese ◽

Diana Alicia Jerusalinsky ◽

...

Keyword(s):

Herpes Simplex Virus ◽

Respiratory Syncytial Virus ◽

Herpes Simplex ◽

Low Ph ◽

Vaginal Mucosa ◽

Ph Values ◽

Syncytial Virus ◽

Simplex Virus ◽

Herpes Simplex Virus 2 ◽

Hiv 1

ABSTRACTHistidine-rich glycoprotein (HRG) is an abundant plasma protein with a multidomain structure, allowing its interaction with many ligands, including phospholipids, plasminogen, fibrinogen, IgG antibodies, and heparan sulfate. HRG has been shown to regulate different biological responses, such as angiogenesis, coagulation, and fibrinolysis. Here, we found that HRG almost completely abrogated the infection of Ghost cells, Jurkat cells, CD4+T cells, and macrophages by HIV-1 at a low pH (range, 6.5 to 5.5) but not at a neutral pH. HRG was shown to interact with the heparan sulfate expressed by target cells, inhibiting an early postbinding step associated with HIV-1 infection. More importantly, by acting on the viral particle itself, HRG induced a deleterious effect, which reduces viral infectivity. Because cervicovaginal secretions in healthy women show low pH values, even after semen deposition, our observations suggest that HRG might represent a constitutive defense mechanism in the vaginal mucosa. Of note, low pH also enabled HRG to inhibit the infection of HEp-2 cells and Vero cells by respiratory syncytial virus (RSV) and herpes simplex virus 2 (HSV-2), respectively, suggesting that HRG might display broad antiviral activity under acidic conditions.IMPORTANCEVaginal intercourse represents a high-risk route for HIV-1 transmission. The efficiency of male-to-female HIV-1 transmission has been estimated to be 1 in every 1,000 episodes of sexual intercourse, reflecting the high degree of protection conferred by the genital mucosa. However, the contribution of different host factors to the protection against HIV-1 at mucosal surfaces remains poorly defined. Here, we report for the first time that acidic values of pH enable the plasma protein histidine-rich glycoprotein (HRG) to strongly inhibit HIV-1 infection. Because cervicovaginal secretions usually show low pH values, our observations suggest that HRG might represent a constitutive antiviral mechanism in the vaginal mucosa. Interestingly, infection by other viruses, such as respiratory syncytial virus and herpes simplex virus 2, was also markedly inhibited by HRG at low pH values, suggesting that extracellular acidosis enables HRG to display broad antiviral activity.

Download Full-text

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

CrossRef Listing of Deleted DOIs ◽

10.1177/108705719900400408 ◽

1999 ◽

Vol 4 (4) ◽

pp. 205-214 ◽

Cited By ~ 19

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.

Download Full-text