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Journal of Virology, September 2003, p. 9845-9851, Vol. 77, No. 18
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.18.9845-9851.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Prolonged Exposure to Progesterone Prevents Induction of Protective Mucosal Responses following Intravaginal Immunization with Attenuated Herpes Simplex Virus Type 2

Amy E. Gillgrass, Ali A. Ashkar, Kenneth L. Rosenthal, and Charu Kaushic*

Center of Gene Therapeutics, Department of Pathology and Molecular Medicine, McMaster University Health Sciences Center, Hamilton, Ontario, Canada

Received 23 April 2003/ Accepted 23 June 2003

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.

* Corresponding author. Mailing address: Department of Pathology and Molecular Medicine, HSC, 4H30F, McMaster University, 1200 Main St. West, Hamilton, Ontario, Canada L8P 3Z5. Phone: (905) 525-9140, ext. 22988. Fax: (905) 522-6750. E-mail: kaushic{at}mcmaster.ca.

Journal of Virology, September 2003, p. 9845-9851, Vol. 77, No. 18
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.18.9845-9851.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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