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

单纯疱疹病毒 2 型发病机制数学模型的强化验证

基本信息

批准号：
8628030
负责人：
Joshua Tisdell Schiffer
金额：
$ 12.8万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-01 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8628030
关键词：
Afferent Neurons Africa Anatomy Antigen-Presenting Cells Antiviral Agents Area Award Biopsy CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cell Density Cells Clinical Clinical Research Clinical Trials Communicable Diseases Data Development Drug resistance Environment Epidemic Epidemiology Epithelial Cells Fellowship Frequencies Funding Ganglia Genital system Goals HIV HIV Seropositivity HIV-1 Heterogeneity Hour Human Human Herpesvirus 2 Immune Immune response Individual Infection Infiltration Kinetics Laboratories Lesion Life Cycle Stages Link Longevity Lymphocyte antigen Measurement Measures Mentors Modeling Mucosal Immunity Mucous Membrane Neurons Outcome Participant Pathogenesis Patients Peripheral Persons Phase Plasma Production Protocols documentation Recurrence Regulation Relative (related person)Research Risk Factors Running Sampling Sampling Studies Severities Sexual Transmission Simplexvirus Simulate Source Staging Structure Study Subject Surface Swab T-Lymphocyte Techniques Time Training Programs Ulcer Universities Validation Viral Viral Load result Virus Washington Work antiretroviral therapy base career density design genital herpes insight mathematical model novel particle public health relevance response transmission process viral detection

项目摘要

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.

描述（由申请人提供）：Joshua T Schiffer 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。该提案描述了一个为期 5 年的培训计划，这将使他能够发展独立的学术能力从事生殖器单纯疱疹病毒 2 (HSV-2) 感染的临床研究和数学建模工作。 Lawrence Corey 博士是 HSV-2 临床研究领域国际知名的领导者，也是该奖项的导师。 HSV-2 是全世界生殖器溃疡最常见的原因，并已成为感染和传播 HIV 的重要危险因素。 HSV-2 传播最常发生在无症状生殖器脱落期间。我们的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事件持续时间不到 12 小时，这表明神经节的频繁重新激活率和快速的外周免疫反应。我们最近设计了一种新的 HSV 复制和免疫反应数学模型，该模型适合从生殖器病变期间进行的日常生殖器拭子采集的定量 HSV PCR 数据。然后该模型以随机形式运行 365 天，得出了有关发病机制的新假设。当前提案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其中的几个假设，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 阴性参与者中收集数据的方案。在目标 2 中，我们建议在参与者连续脱落事件之前进行活检，并在其期间推导模型参数。我们试图证明 CD8+ T 细胞扩增只会在病灶脱落发作期间发生，但不会在较小的低拷贝脱落发作期间发生，并且发作时的 CD8+ T 细胞密度与病灶大小和峰值 HSV 拷贝数呈负相关。在目标 3 中，我们将对患者进行为期 60 天的集中拭子检测，以确定脱落频率，并进行一年的临床随访以确定复发频率。然后，我们将使用预测模型来确定预测这些结果的异质性的模型参数。公共健康相关性：该模型在建模领域是新颖的，基于其随机格式、其对粘膜免疫的关注以及其与详细的连续定量病毒学和免疫细胞数据的紧密联系。我们当前资助申请的目标是通过研究对象的密集临床采样以及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。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Predictors of hepatitis B cure using gene therapy to deliver DNA cleavage enzymes: a mathematical modeling approach.

DOI：
10.1371/journal.pcbi.1003131
发表时间：
2013
期刊：
PLoS computational biology
影响因子：
4.3
作者：
Schiffer JT;Swan DA;Stone D;Jerome KR
通讯作者：
Jerome KR

HSV-2 serology can be predictive of HIV epidemic potential and hidden sexual risk behavior in the Middle East and North Africa.

DOI：
10.1016/j.epidem.2010.08.003
发表时间：
2010-12
期刊：
EPIDEMICS
影响因子：
3.8
作者：
Abu-Raddad, Laith J.;Schiffer, Joshua T.;Ashley, Rhoda;Mumtaz, Ghina;Alsallaq, Ramzi A.;Akala, Francisca Ayodeji;Semini, Iris;Riedner, Gabriele;Wilson, David
通讯作者：
Wilson, David