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* Department of Obstetrics, Gynecology, and Reproductive Sciences,
Graduate Program in Immunology, and
Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213
Clinical research suggests hormonal contraceptive use is associated with increased frequencies of HSV reactivation and shedding. We examined the effects of medroxyprogesterone acetate (MPA), the compound most commonly used for injectable hormonal contraception, on HSV type 1 (HSV-1) reactivation and CD8+ T cell function in murine trigeminal ganglia (TG). In ex vivo TG cultures, MPA dramatically inhibited canonical CD8+ T cell effector functions, including IFN-
production and lytic granule release, and increased HSV-1 reactivation from latency. In vivo, MPA treatment of latently infected ovariectomized mice inhibited IFN- production and lytic granule release by TG resident CD8+ T cells stimulated directly ex vivo. RNA specific for the essential immediate early viral gene ICP4 as well as viral genome DNA copy number were increased in mice that received MPA during latency, suggesting that treatment increased in vivo reactivation. The increase in HSV-1 copy number appeared to be the result of a two-tine effect, as MPA induced higher reactivation frequencies from latently infected explanted TG neurons in the presence or absence of CD45+ cells. Our data suggest hormonal contraceptives that contain MPA may promote increased frequency of HSV reactivation from latency through the combinatory effects of inhibiting protective CD8+ T cell responses and by a leukocyte-independent effect on infected neurons.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Grants K23 AI064396 (to T.L.C.), T32 AI 060525 (to B.S.S.), R01 EY05945 and P30EY08098 (to R.L.H.) from the National Institutes of Health, by an unrestricted grant from Research to Prevent Blindness (New York, NY), and by the Eye and Ear Foundation of Pittsburgh.
2 Address correspondence and reprint requests to Dr. Thomas L. Cherpes, Magee Womens Research Institute, 204 Craft Avenue, Room A524, Pittsburgh, PA 15213. E-mail address: cherpestl{at}upmc.ecu
3 Abbreviations used in this paper: HSV-1, HSV type 1; MPA, medroxyprogesterone acetate; TG, trigeminal ganglia; gB, glycoprotein B; dpi, days postinfection.
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