Protective immunity against HSV-2 in the mouse vagina

Parr, Margaret B.; Parr, Earl L.

doi:10.1016/s0165-0378(97)00055-7

Cited by 37 publications

(18 citation statements)

References 54 publications

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“…Mice depleted of T cells are unable to resolve a genital HSV infection, but mice depleted of either CD4 ϩ or CD8 ϩ subset can ultimately resolve the infection, although clearance is delayed (24,28,30,(34)(35). HSV-specific T cells exhibiting ex vivo cytolytic function have been isolated from the vaginal lumen of HSV-2-inoculated mice at a time concomitant with virus clearance (32).…”

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confidence: 99%

Clearance of Herpes Simplex Virus Type 2 by CD8⁺T Cells Requires Gamma Interferon and either Perforin- or Fas-Mediated Cytolytic Mechanisms

Dobbs¹,

Strasser²,

Chu³

et al. 2005

J Virol

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The T-cell-mediated resolution of herpes simplex virus type 2 (HSV-2) genital infections is not fully understood. In these studies, the mechanisms by which CD8 ؉ T cells clear virus from the genital epithelium were examined. Ovalbumin (OVA)-specific CD8 ؉ T cells from OT-I transgenic mice cleared a thymidine kinase-deficient, ovalbumin-expressing HSV-2 virus (HSV-2 tk ؊ OVA) from the genital epithelium of recipient mice, and clearance was abrogated by in vivo neutralization of gamma interferon (IFN-␥). Further, CD8؉ OT-I T cells deficient in IFN-␥ were unable to clear HSV-2 tk ؊ OVA from the vaginal epithelium. The requirement for cytolytic mechanisms in HSV-2 tk ؊ OVA clearance was tested in radiation chimeras by adoptive transfer of wild-type or perforin-deficient OT-I T cells to irradiated Fas-defective or wild-type recipients. Although a dramatic decrease in viral load was observed early after challenge with HSV-2 tk ؊ OVA, full resolution of the infection was not achieved in recipients lacking both perforin-and Fas-mediated cytolytic pathways. These results suggest that IFN-␥ was responsible for an early rapid decrease in HSV-2 virus titer. However, either perforin-or Fas-mediated cytolytic mechanisms were required to achieve complete clearance of HSV-2 from the genital epithelium.Herpes simplex virus type 2 (HSV-2) infects epithelial cells in the genital mucosa, spreads to the sensory ganglia via retrograde transport, and establishes a lifelong latent infection in sensory neurons (50). The virus periodically reactivates and descends sensory neurons via anterograde transport, resulting in development of recurrent lesions at or near the site of primary infection or in shedding of infectious virus in the absence of disease symptoms. The primary and recurrent lesions of immunocompetent individuals are generally self limiting and are resolved primarily by cell-mediated immune mechanisms. Recurrent disease is less well controlled in immunocompromised individuals, resulting in more frequent recurrences and sometimes severe mucocutaneous disease manifestations. Studies of HSV infection in human immunodeficiency virus (HIV)-infected individuals suggested that the severity of HSV disease could be inversely correlated with the number of HSV-specific CD8 ϩ T cells (39). Studies of recurrent HSV lesions in immunocompetent humans have demonstrated the early infiltration of CD4 ϩ T cells and macrophages, local production of IFN-␥, and late arrival of CD8ϩ T cells at the site of HSV infection. Both CD4 ϩ and CD8 ϩ T lymphocytes capable of IFN-␥ secretion and HSVspecific cytolysis have been isolated from human herpetic lesions (10) and clearance of infectious virus, and resolution of lesions has been correlated with the detection of HSV-specific cytolytic T-lymphocyte activity (10, 22-23). However, the role for these cytolytic and noncytolytic immune mechanisms in resolution of HSV-2 genital infections is not well understood.Murine models of HSV-2 genital infection have also demonstrated the importance of cell-mediated imm...

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confidence: 99%

Clearance of Herpes Simplex Virus Type 2 by CD8⁺T Cells Requires Gamma Interferon and either Perforin- or Fas-Mediated Cytolytic Mechanisms

Dobbs¹,

Strasser²,

Chu³

et al. 2005

J Virol

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“…Evidence of an increasing incidence and prevalence of HSV-2 infections (12,26,58) suggests that more efficacious control strategies are needed. Clinical infection occurs in 20 to 30% of adults (7,43), while up to 85% of females develop HSV-2 antibodies in their lifetime (20). Recent preclinical studies have suggested that direct application of vaccines or microbicides to the vaginal mucosa may offer an alternative to traditional chemotherapy (5,8,13,30,43).…”

mentioning

confidence: 99%

“…Clinical infection occurs in 20 to 30% of adults (7,43), while up to 85% of females develop HSV-2 antibodies in their lifetime (20). Recent preclinical studies have suggested that direct application of vaccines or microbicides to the vaginal mucosa may offer an alternative to traditional chemotherapy (5,8,13,30,43). Immunotherapy of recurrent HSV-2 infections through vaccination and immunomodulation has been shown to be effective in preliminary clinical trials (26,47,49,50).…”

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confidence: 99%

Use of Immunostimulatory Sequence-Containing Oligonucleotides as Topical Therapy for Genital Herpes Simplex Virus Type 2 Infection

Pyles

Higgins

Chalk³

et al. 2002

J Virol

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Synthetic oligonucleotides containing CpG motifs in specific sequence contexts have been shown to induce potent immune responses. We have evaluated mucosal administration of two immunostimulatory sequence (ISS)-containing phosphorothioate-stabilized oligonucleotides for antiherpetic efficacy in animal models. The ISS oligonucleotides, suspended in phosphate-buffered saline, were tested in mouse and guinea pig vaginal models of herpes simplex virus type 2 (HSV-2) infection. For comparison, groups of untreated, non-ISS oligonucleotide-treated, and acyclovir-treated animals also were monitored. The results indicated that vaginal epithelial application of ISS (up to 6 h after viral inoculation) with mice lethally challenged with HSV-2 delayed disease onset and reduced the number of animals that developed signs of disease (P ‫؍‬ 0.003). ISS application significantly increased survival rates over those of controls (P ‫؍‬ 0.0014). The ISS also impacted an established infection in the guinea pig model of HSV-2 disease. A single administration of ISS (21 days after viral inoculation) significantly reduced the frequency and severity of HSV-2 lesions compared to results with non-ISS oligonucleotide-treated and untreated guinea pigs (P < 0.01). HSV-2 is shed from the vaginal cavity of the guinea pig in the absence of lesions, similar to the case with humans. As an additional indication of ISS efficacy, the magnitude of viral shedding also was significantly reduced in ISS-treated animals (P < 0.001). These effects appeared to be immunologically mediated, since ISS had no direct effect on HSV-2 replication in vitro using standard plaque assays. These data suggest that ISS may be useful in the treatment and control of genital herpes in humans.

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“…Most migrating cells appear to be lymphoid in nature with no evidence that macrophages or Langerhans cells are trafficking out of the tissue (14). Although the initial infection of the genital tract by HSV-2 in progesterone-treated mice appears to be similar to the initial infection in humans, susceptible epithelial cells in mice are present in both vagina and cervix whereas they are mainly in the cervix of humans (15). The infection is controlled by local innate and adaptive immunity including neutrophils (16) and CTLs (17)(18)(19)(20).…”

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confidence: 99%

“…Vaccine development is ongoing to generate a protective IgG response against HSV-2 as IgA is not required for protection against vaginal HSV-2 infection (15,23,24). Vaccines using recombinant HSV-2 glycoproteins including glycoprotein (g)B and gD have been found to provide adequate protection against subsequent vaginal infection with HSV-2 in a guinea pig model (25) but clinical outcomes have not been forthcoming.…”

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confidence: 99%

The Application of a Plasmid DNA Encoding IFN-α1 Postinfection Enhances Cumulative Survival of Herpes Simplex Virus Type 2 Vaginally Infected Mice

Härle

Noisakran

Carr

2001

The Journal of Immunology

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Using a hormonally induced susceptibility mouse model to investigate vaginal HSV type 2 (HSV-2) infection, a study was undertaken to determine the efficacy of a plasmid DNA encoding IFN-α1 introduced into the vaginal lumen postinfection (PI). Mice infected with HSV-2 intravaginally and treated intravaginally 24 h later with 100 μg DNA encoding IFN-α1 showed enhanced survival (10/15) in comparison to mice treated with 100 μg plasmid DNA vector alone (3/10) or vehicle (4/27). In contrast, mice receiving recombinant IFN-αA (5–500 U/vagina) 24 h PI showed no significant survival in comparison to the vehicle (saline)-treated group. The protective effect was time dependent in that mice receiving the IFN-α1 transgene 48 h PI succumbed at a rate similar to the plasmid DNA vector-treated group. The increase in cumulative survival elicited by the transgene corresponded with a reduction in viral replication and Ag expressed in the vaginal epithelium early (i.e., 3 days PI) during acute infection and replicating virus recovered in the spinal cord day 7 PI. By day 7 PI, HSV-2 glycoprotein B transcript expression was no longer detectable in vaginal tissue from the IFN-α1 transgene-treated group (0/8) compared with levels expressed in plasmid vector-treated controls (4/6 mice surveyed were positive). Collectively, these results suggest the application of DNA encoding type I IFN is an effective and alternative approach to currently prescribed therapies in controlling vaginal HSV-2 infection by antagonizing viral replication.

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Protective immunity against HSV-2 in the mouse vagina

Cited by 37 publications

References 54 publications

Clearance of Herpes Simplex Virus Type 2 by CD8⁺T Cells Requires Gamma Interferon and either Perforin- or Fas-Mediated Cytolytic Mechanisms

Clearance of Herpes Simplex Virus Type 2 by CD8⁺T Cells Requires Gamma Interferon and either Perforin- or Fas-Mediated Cytolytic Mechanisms

Use of Immunostimulatory Sequence-Containing Oligonucleotides as Topical Therapy for Genital Herpes Simplex Virus Type 2 Infection

The Application of a Plasmid DNA Encoding IFN-α1 Postinfection Enhances Cumulative Survival of Herpes Simplex Virus Type 2 Vaginally Infected Mice

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Protective immunity against HSV-2 in the mouse vagina

Cited by 37 publications

References 54 publications

Clearance of Herpes Simplex Virus Type 2 by CD8+T Cells Requires Gamma Interferon and either Perforin- or Fas-Mediated Cytolytic Mechanisms

Clearance of Herpes Simplex Virus Type 2 by CD8+T Cells Requires Gamma Interferon and either Perforin- or Fas-Mediated Cytolytic Mechanisms

Use of Immunostimulatory Sequence-Containing Oligonucleotides as Topical Therapy for Genital Herpes Simplex Virus Type 2 Infection

The Application of a Plasmid DNA Encoding IFN-α1 Postinfection Enhances Cumulative Survival of Herpes Simplex Virus Type 2 Vaginally Infected Mice

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Clearance of Herpes Simplex Virus Type 2 by CD8⁺T Cells Requires Gamma Interferon and either Perforin- or Fas-Mediated Cytolytic Mechanisms

Clearance of Herpes Simplex Virus Type 2 by CD8⁺T Cells Requires Gamma Interferon and either Perforin- or Fas-Mediated Cytolytic Mechanisms