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

描述(由申请者提供)：约书亚·T·希弗博士将于2009年在华盛顿大学完成传染病奖学金和流行病学硕士学位。这项建议描述了一个为期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。劳伦斯·科里博士是国际知名的HSV-2临床研究领导者，也是该奖项的导师。单纯疱疹病毒2型是全世界生殖器溃疡最普遍的原因，已成为感染和传播艾滋病毒的重要风险因素。HSV-2传播最常发生在无症状生殖器脱落期间。我们小组最近使用密集采样(每天擦拭生殖器表面4次)来证明大多数生殖器脱落持续时间不到12小时，这表明神经节经常重新激活，外周免疫反应活跃。我们最近设计了一种新的HSV复制和免疫反应的数学模型，该模型适用于来自生殖器病变期间每日生殖器拭子的定量HSV聚合酶链式反应数据。该模型随后以随机形式运行了365天，从而得出了关于发病机制的新假说。当前建议的目标是将我们的模型与更详细的前瞻性收集的数据联系起来，以证明其中几个假设，这些数据包括来自频繁生殖器PCR拭子的HSV拷贝数、来自连续活检的CD8+T细胞密度以及来自照片和连续测量的病变大小。我们还将使用实验技术获得患者的个人参数值。目标1描述了我们收集20名HIV阳性和20名HIV阴性参与者的数据的方案。在目标2中，我们建议在参与者连续脱落之前进行活检，并在连续脱落期间推导模型参数。我们试图证明，CD8+T细胞仅在皮损脱落期间发生，而不会发生在较小的低拷贝脱落期间，并且发病时CD8+T细胞密度与病变大小和HSV峰值拷贝数呈负相关。在目标3中，我们将对患者进行为期60天的密集拭子检查，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，预测这些结果中的异质性。 公共卫生相关性：该模型在建模领域是新颖的，其基础是随机格式，其重点是粘膜免疫，以及其与详细的顺序定量病毒学和免疫细胞数据的紧密联系。我们目前资金申请的目标是通过对研究对象的密集临床采样和对模型参数的个性化实验室验证来验证模型的初始预测和参数估计。

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.