Intense Validation of a Mathematical Model of Herpes Simplex Virus-2 Pathogenesis

描述（由申请人提供）：Joshua T Schiffer博士将于2009年在华盛顿大学获得传染病学奖学金和流行病学硕士学位。该提案描述了一个为期5年的培训计划，这将使他能够在生殖器单纯疱疹病毒-2 （HSV-2）感染的临床研究和数学建模方面发展独立的学术生涯。Lawrence Corey博士是2型单纯疱疹临床研究领域的国际知名领导者，也是该奖项的导师。2型单纯疱疹病毒是全世界生殖器溃疡最普遍的原因，并已成为艾滋病毒感染和传播的一个重要危险因素。2型单纯疱疹病毒传播最常发生在无症状生殖器脱落期间。我们的研究小组最近进行了密集取样（每天4次擦拭生殖器表面），以证明大多数生殖器脱落事件持续不到12小时，这表明神经节的频繁再激活率和活跃的外周免疫反应。我们最近设计了一个新的HSV复制和免疫反应的数学模型，我们适合于从生殖器病变期间进行的日常生殖器拭子提取的定量HSV PCR数据。然后，该模型以随机格式运行365天，导致关于发病机制的新假设。当前建议的目标是通过将我们的模型与更详细的前瞻性收集的数据联系起来来证明这些假设，包括从频繁的生殖器PCR拭子中获得的HSV拷贝数，从连续活检中获得的CD8+ t细胞密度，以及从照片和连续测量中获得的病变大小。我们还将使用实验技术获得患者的个体参数值。目标1描述了我们在20名HIV阳性和20名HIV阴性参与者中收集这些数据的方案。在目标2中，我们建议在参与者的连续脱落事件之前进行活检，并在此期间推导模型参数。我们试图证明CD8+ t细胞扩增只会发生在病变脱落期，而不会发生在较小的低拷贝脱落期，并且发病时CD8+ t细胞密度与病变大小和峰值HSV拷贝数呈负相关。在Aim 3中，我们将密集拭子患者60天以确定脱落频率，并临床随访一年以确定复发频率。然后，我们将使用预测模型来确定模型参数，预测这些结果的异质性。

DESCRIPTION (provided by applicant): Dr. Joshua T Schiffer is completing Infectious Diseases fellowship and an MS degree in Epidemiology at the University of Washington in 2009. This proposal describes a 5-year training program, which will allow him to develop an independent academic career in clinical research and mathematical modeling of genital herpes simplex virus-2 (HSV-2) infection. Dr. Lawrence Corey is an internationally renowned leader in clinical HSV-2 research and is the mentor for this award. HSV-2 is the most prevalent cause of genital ulcers worldwide and has emerged as a significant risk factor for acquisition and transmission of HIV. HSV-2 transmission most frequently occurs during periods of asymptomatic genital shedding. Our group has recently used intensive sampling (swabbing the genital surfaces 4 times per day) to demonstrate that the majority of genital shedding episodes last less than 12 hours, suggesting a frequent reactivation rate from the ganglia and a brisk peripheral immune response. We recently designed a novel mathematical model of HSV replication and immune response that we fit to quantitative HSV PCR data derived from daily genital swabs performed during a genital lesion. The model was then run in a stochastic format over 365 days leading to novel hypotheses regarding pathogenesis. The goal of the current proposal is to prove several of these hypotheses by linking our model to more detailed prospectively gathered data including HSV copy number from frequent genital PCR swabs, CD8+ T-cell density from serial biopsies, and lesion size from photographs and serial measurements. We will also obtain individual parameter values for patients using experimental techniques. Aim 1 describes our protocol for gathering this data in 20 HIV positive and 20 HIV negative participants. In Aim 2, we propose performing biopsies before, and deriving model parameters during, successive shedding episodes in our participants. We seek to prove that CD8+ T-cell expansion will occur only during lesional shedding episodes but not during smaller low-copy shedding episodes, and that CD8+ T-cell density at episode onset inversely correlates with lesion size and peak HSV copy number. In Aim 3, we will swab patients intensively for 60 days to determine shedding frequency, and follow clinically for a year to determine recurrence frequency. We will then use prediction models to determine model parameters predict heterogeneity in these outcomes. PUBLIC HEALTH RELEVANCE: The model is novel in the modeling field based on it stochastic format, its focus on mucosal immunity, and on its tight linkage to detailed sequential quantitative virologic and immune cell data. The goal of our current funding application is to validate the model's initial prediction and parameter estimates with intensive clinical sampling of study subjects, and individualized laboratory verification of model parameters.