Analysis of Herpes Simplex Virus-Specific T Cells in the Murine Female Genital Tract Following Genital Infection with Herpes Simplex Virus Type 2

AbstractA murine model of genital infection with a thymidine kinase-deficient (tk-) strain of herpes simplex virus type 2 (HSV-2) was utilized to examine the development of the local T cell response in the genital mucosa and draining genital lymph nodes (gLN). HSV-specific cytokine-secreting T cells were detected in the gLN 4 days postintravaginal inoculation but not in the urogenital tract or spleen until 5 days postinoculation, suggesting the cellular immune response originates in the gLN. More CD4+ than CD8+ gLN T cells were detected by flow cytometric analysis following primary vaginal inoculation and the majority of HSV-specific gLN T cells detected by ELISPOT were CD4+ and Th1-like based on secretion of IFNγ and not IL-4 or IL-5. A similar population of HSV-specific memory T cells persisted in the genital tract 2 months following HSV-2 tk- genital inoculation. These data suggest that the urogenital cellular immune response elicited in mice following genital inoculation with HSV-2 tk- is predominantly CD4+ and Th1-like, resembling that observed in humans. The results of this study are important for the rational design of vaccines capable of inducing protective immunity in the genital tract

Status of vaccine research and development of vaccines for Nipah virus

AbstractNipah virus (NiV) is a highly pathogenic, recently emerged paramyxovirus that has been responsible for sporadic outbreaks of respiratory and encephalitic disease in Southeast Asia. High case fatality rates have also been associated with recent outbreaks in Malaysia and Bangladesh. Although over two billion people currently live in regions in which NiV is endemic or in which the Pteropus fruit bat reservoir is commonly found, there is no approved vaccine to protect against NiV disease. This report examines the feasibility and current efforts to develop a NiV vaccine including potential hurdles for technical and regulatory assessment of candidate vaccines and the likelihood for financing

Vaccinology: an essential guide

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Effector CD4+ T-Cell Involvement in Clearance of Infectious Herpes Simplex Virus Type 1 from Sensory Ganglia and Spinal Cords ▿

In primary infection, CD8+ T cells are important for clearance of infectious herpes simplex virus (HSV) from sensory ganglia. In this study, evidence of CD4+ T-cell-mediated clearance of infectious HSV type 1 (HSV-1) from neural tissues was also detected. In immunocompetent mice, HSV-specific CD4+ T cells were present in sensory ganglia and spinal cords coincident with HSV-1 clearance from these sites and remained detectable at least 8 months postinfection. Neural CD4+ T cells isolated at the peak of neural infection secreted gamma interferon, tumor necrosis factor alpha, interleukin-2 (IL-2), or IL-4 after stimulation with HSV antigen. HSV-1 titers in neural tissues were greatly reduced over time in CD8+ T-cell-deficient and CD8+ T-cell-depleted mice, suggesting that CD4+ T cells could mediate clearance of HSV-1 from neural tissue. To examine possible mechanisms by which CD4+ T cells resolved neural infection, CD8+ T cells were depleted from perforin-deficient or FasL-defective mice. Clearance of infectious virus from neural tissues was not significantly different in perforin-deficient or FasL-defective mice compared to wild-type mice. Further, in spinal cords and brains after vaginal HSV-1 challenge of chimeric mice expressing both perforin and Fas or neither perforin nor Fas, virus titers were significantly lower than in control mice. Thus, perforin and Fas were not required for clearance of infectious virus from neural tissues. These results suggest that HSV-specific CD4+ T cells are one component of a long-term immune cell presence in neural tissues following genital HSV-1 infection and play a role in clearance of infectious HSV-1 at neural sites, possibly via a nonlytic mechanism

Efficacy of genital T cell responses to herpes simplex virus type 2 resulting from immunization of the nasal mucosa

AbstractIntravaginal (ivag) or intranasal (i.n.) immunization of C57BL/6J (B6) mice with a thymidine kinase-deficient strain (tk−) of herpes simplex virus type 2 (HSV-2) resulted in comparable protection of the genital epithelium and sensory ganglia against HSV-2 challenge. In contrast, protection of these sites was much reduced in i.n.-immunized compared to ivag-immunized B cell-deficient μMT mice. Fewer HSV-specific T cells were detected in the genital epithelium of i.n.-immunized compared to ivag-immunized μMT mice after HSV-2 challenge. Passive transfer of HSV-specific serum to immune μMT mice restored protection of these sites against HSV-2 challenge. These results suggest that protection of genital and neuronal sites may be conferred by i.n. immunization but may be more dependent on antibody-dependent mechanisms than the protection resulting from genital immunization. These results have implications for immunization strategies to elicit high levels of cell-mediated protection of the genital tract and sensory ganglia

Efficacy and Toxicity of Zinc Salts as Candidate Topical Microbicides against Vaginal Herpes Simplex Virus Type 2 Infection

Zinc salt solutions administered as topical microbicides provided significant protection against herpes simplex virus type 2 infection in a mouse vaginal challenge model. However, at the therapeutic concentration, the salt solutions caused sloughing of sheets of vaginal epithelial cells. These observations limit the utility of zinc salts as microbicides and suggest that the application of zinc solutions to mucosal surfaces has the potential to cause damage that might increase susceptibility to secondary infections at a later time

Tissue distribution of HSV-2 specific memory T cells following genital HSV-2 infection of guinea pigs.

<p>Hartley guinea pigs were infected ivag with HSV-2 strain MS and lymphocytes isolated from the indicated tissues on days 99-150 post infection. HSV-specific, IFN-γ SCs were detected and quantified by IFN-γ ELISPOT. The frequency of HSV-specific, IFN-γ SC per 10⁶ cells is given in <b>A,C,E,G</b> and the total number of HSV-specific, IFN-γ SC is given in <b>B,D,F,H</b> for each tissue. Each data point represents results from an individual animal. (* <i>P</i><0.05; ** <i>P</i><0.01, Student's <i>t</i> test; *** <i>P</i><0.0001, Chi square).</p