Pathogenesis of HSV-1/2 induced vaginitis/vulvitis of the mouse: dependence of lesions on genetic properties of the virus and analysis of pathohist… – PubMed

Pathogenesis of HSV-1/2 induced vaginitis/vulvitis of the mouse: dependence of lesions on genetic properties of the virus and analysis of pathohist... - PubMed

SPL7013 Gel (VivaGel®) is a microbicide in development for prevention of HIV and HSV. Even in the presence of high titers of HSV-specific Ab, T cell-dependent mechanisms were required for protection of the vaginal mucosae of HSV-immune mice and could be detected by 24 h after intravaginal reinoculation. Subcutaneous immunization of C57BL/6 or BALB/c mice with ΔgD(-/+gD1) provided 100% protection against lethal intravaginal or skin challenges and prevented latency. Nonoxynol-9 induced an inflammatory response characterized by increases in levels of cytokines and chemokines, recruitment of neutrophils and monocytes into the genital tract, and activation of the transcription factors NF-κB and activator protein—1. In spite of this, the number of latently infected animals did not vary significantly in the mouse strains. In rare instances, a publisher has elected to have a “zero” moving wall, so their current issues are available in JSTOR shortly after publication. Co-culturing stromal cells did not significantly change levels of viral shedding from ECs.

Pathogenesis of HSV-1/2 induced vaginitis/vulvitis of the mouse: dependence of lesions on genetic properties of the virus and analysis of pathohist... - PubMed
vaginalis (IRR, 2.3 [95% CI, 1.3-4.2]), and syphilis (IRR, 4.7 [95% CI, 1.1-19.9]). Grade 1 was macroscopically characterized by a slight inflammation commencing on days 5-6. Understanding the underlying mechanisms by which HSV-2 facilitates HIV-1 infection and optimizing the efficacy of therapies to inhibit HIV-1 infection during HSV-2 coinfection should contribute to reducing HIV-1 transmission. HSV-antigens were only detected above the basal membrane, and some infiltration with granulocytes and lymphocytes was observed below the basal membrane at day 4. CVF samples obtained immediately after dosing almost completely inhibited (median, interquartile range) HIV-1 [96% (95,97)] and HSV-2 [86% (85,94)], and activity was maintained in all women at 3 h (HIV-1 [96% (95,98), p = 0.9]; HSV-2 [94% (91,97), p = 0.005]). Cellular infiltrates were present in the large antigen containing epithelial lesions and below the basal membrane. From day 4 on, neurons were HSV-antigen and DNA positive and macrophages in the stroma contained antigen.

These studies highlight the need for novel prevention strategies active against both viruses.Vaginal microbicides are one of the most promising preventive interventions [9]. Grade 3 exhibited prolonged severe hyperemia, and destruction of the epithelium and the stroma with necrosis and infiltration, especially of the vulva. This grading system was shown to depend on certain unknown genetic properties of HSV-strains. Neither thymidine-kinase activity, replication in macrophages, fusion activity of strains nor presence or absence of the Hpa I P-fragment were shown to be of importance for severity of vaginitis/vulvitis. Vaginitis/vulvitis was shown to be an all or none response to HSV independent of the rate of replication. The set of virus genes responsible for neuroinvasiveness after vaginal or i.p. inoculation was found to be different.

The time course of replication (mainly days 3-6) and inflammation (days 5-10) indicates that inflammation seems to be a secondary immunological phenomenon induced later by the replication phase of HSV. Vaginally applied microbicide agents offer a potential strategy for prevention of the sexual transmission of HIV or other sexually transmitted infections (STIs) that can be initiated by women.

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