Background Herpes simplex virus (HSV) remains latent in nerve root ganglia of infected persons and is thought to reactivate several times yearly. Recent in situ data show the localization of HSV-specific CD8+ T cells at the dermal epidermal junction next to peripheral sensory nerve endings, suggesting that viral reactivation may occur more frequently than previously appreciated. Methods Twenty-five HSV-2–seropositive and 18 HSV-1–seropositive healthy adults collected anogenital and oral swabs, respectively, 4 times per day for 60 days. Swabs were assayed for HSV, using a quantitative polymerase chain reaction assay. Results Twenty-four percent of anogenital reactivations and 21% of oral reactivations lasted ≤6 h, and 49% of anogenital reactivations and 39% of oral reactivations lasted ≤12 h. Lesions were reported in only 3 (7%) of 44 anogenital reactivations and 1 (8%) of 13 oral reactivations lasting ≤12 h. The median HSV DNA levels at initial and last detection were 103.5 and 103.3 copies/mL, respectively, during anogenital reactivation and 103.7 and 103.0 copies/mL, respectively, during oral reactivation. Conclusions This high frequency of short subclinical HSV reactivation in immunocompetent hosts strongly suggests that the peripheral mucosal immune system plays a critical role in clearing HSV reactivations.

Herpes Simplex Virus-2 (HSV-2) is a sexually transmitted infection that is the leading cause of genital ulcers worldwide. Infection is life long and is characterized by repeated asymptomatic and symptomatic shedding episodes of virus that are initiated when virus is released from neurons into the genital tract. The pattern of HSV-2 release from neurons into the genital tract is poorly understood. We fit a mathematical model of HSV-2 pathogenesis to curves generated from daily quantification of HSV in mucosal swabs performed from patients with herpetic genital ulcers. We used virologic parameters derived from model fitting for stochastic model simulations. These simulations reproduced previously documented estimates for shedding frequency, and herpetic lesion diameter and frequency. The most realistic model output occurred when we assumed minimal amounts of daily neuronal virus introduction. In our simulations, small changes in average total quantity of HSV-2 released from neurons influenced detectable shedding frequency, while changes in frequency of neuronal HSV-2 release had little effect. Frequent HSV-2 shedding episodes in humans are explained by nearly constant release of small numbers of viruses from neurons that terminate in the genital tract.Corresponding author: Joshua T. Schiffer, MD, MSc, Fred Hutchinson Cancer Research Center, Vaccine and Infectious Disease Institute and Program in Infectious Diseases, 1616 Eastlake Ave., Seattle, WA 98102, jschiffe@fhcrc.org,. Author contributions: JTS conceived the project, designed the model, performed the analyses and wrote the manuscript; LAR designed the model and edited the manuscript; KM performed shedding studies and edited the manuscript; JZ performed staining for CD8+ lymphocytes; SS arranged the data for analysis; AA assisted with data analysis; AW performed shedding studies and edited the manuscript; LC conceived the project, analyzed the data and edited the mansucript.Competing interests: The authors declare that they have no competing financial interests. Supplementary MaterialMethods (15 pages), Supplementary Figures 1-5, References, and Four files [a graphical display of 115 curves of combined anogenital swabs from patients with genital lesions (SM1), the data needed to generate these curves (SM2), code for the mathematical model in Berkeley Madonna Version 8.3.18 (SM3) and in Word format (SM4 Herpes Simplex Virus-2 (HSV-2) is a widely prevalent sexually transmitted infection that is the leading cause of genital ulcer disease (1), and is a risk factor for human immunodeficiency virus-1 (HIV-1) acquisition and transmission (2,3). Initial infection results in viral replication in epithelial cells of the genital tract and spread into innervating peripheral neurons. The virus is not cytopathic to neurons and exists indefinitely in the nuclei of neurons within the dorsal root ganglia in a protected state termed "latency" (4). Virus is released from the neurons back into the genital tract during "reactivations".Until recently, a common view of HSV...