title: Prolonged exposure to progesterone prevents induction of protective mucosal responses following intravaginal immunization with attenuated herpes simplex virus type 2.
abstract: Depo-Provera (Depo) is a long-acting progestational formulation that is a popular form of contraception for women. In animal models of sexually transmitted diseases, it is used to facilitate infection. Here we report that treatment with Depo, in a mouse model of genital herpes simplex virus type 2 (HSV-2), altered immune responses depending on the length of time that animals were exposed to Depo prior to immunization. Mice immunized intravaginally (i.vag.) with an attenuated strain (TK(-)) of HSV-2 following longer (15 days) exposure to Depo (Depo 15 group) failed to show protection when challenged with wild-type HSV-2. In contrast, mice that were immunized shortly after Depo treatment (5 days; Depo 5 group) were fully protected and showed no genital pathology after HSV-2 challenge. High viral titers were detected in the vaginal washes of the Depo 15 group up to 6 days postchallenge. In contrast, no viral shedding was observed beyond day 3 postchallenge in the Depo 5 group. Following i.vag. TK(-) immunization, high levels of gamma interferon (IFN-gamma) were detected locally in vaginal washes of the Depo 5 group but not the Depo 15 group. After HSV-2 challenge, an early peak of IFN-gamma in the Depo 5 group coincided with clearance of the virus. In Depo 15 animals IFN-gamma was present throughout the 6 days postinfection. HSV-2-specific T-cell cytokine responses measured in the lymph node cells of Depo 5 TK(-)-immunized mice indicated a significantly higher Th1 response than that of Depo 15 TK(-)-immunized mice. The protection after HSV-2 challenge in the Depo 5 group correlated with increased local HSV-2 glycoprotein B (gB)-specific immunoglobulin G (IgG) and IgA responses seen in the vaginal secretions. The Depo 15 group had poor gB-specific antibody responses in the genital tract after HSV-2 challenge. These results indicate that longer exposure to Depo leads to poor innate and adaptive immune responses to HSV-2 that fail to protect mice from subsequent genital challenges.
authors.affiliation: Center of Gene Therapeutics, Department of Pathology and Molecular Medicine, McMaster University Health Sciences Center 4H30F, 1200 Main Street West, Hamilton, Ontario, Canada L8P 3Z5.
authors.forename: Amy E
authors.initials: AE
authors.lastname: Gillgrass
authors.forename: Ali A
authors.initials: AA
authors.lastname: Ashkar
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Rosenthal
authors.forename: Charu
authors.initials: C
authors.lastname: Kaushic
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000032:analysis; D005260:Female; D018258:Herpesvirus 2, Human / Q000276:immunology*; D022283:Herpesvirus Vaccines / Q000276:immunology*; D018928:Immunity, Mucosal; D007114:Immunization; D007070:Immunoglobulin A / Q000032:analysis; D007074:Immunoglobulin G / Q000032:analysis; D007371:Interferon-gamma / Q000032:analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D011374:Progesterone / Q000633:toxicity*; D012749:Sexually Transmitted Diseases / Q000517:prevention & control; D013601:T-Lymphocytes / Q000276:immunology; D015164:Vaccines, Inactivated / Q000276:immunology; D014621:Vagina / Q000276:immunology*; D017201:Virus Shedding
chemical_list: D000914:Antibodies, Viral; D022283:Herpesvirus Vaccines; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D015164:Vaccines, Inactivated; D011374:Progesterone; D007371:Interferon-gamma