Dynamic Reactivation of Herpes Simplex Virus-2 and the Genital Mucosal Response

单纯疱疹病毒 2 型的动态再激活和生殖器粘膜反应

基本信息

批准号：
8074906
负责人：
CHRISTINE MICHELLE JOHNSTON
金额：
$ 12.7万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8074906
关键词：
Acyclovir Address Africa South of the Sahara Age Anatomic Sites Antiviral Agents Antiviral Therapy Award Biopsy Cell physiology Chronic Clinical Clinical Research Communicable Diseases Cutaneous Data Detection Disease Dose Epidemic Epidemiology Epithelial Europe FDA approved Fellowship Frequencies Ganglia Gene Expression Gene Proteins Genes Genital system HIV Herpesviridae Hour Human Herpesvirus 2 Immune response Immunocompetent Infant Infection Inflammatory Interferon Type II Lead Lesion Location Mediating Mentors Molecular Profiling Mucous Membrane Oral Participant Pathogenesis Pattern Peripheral Peripheral Nerves Persons Pharmaceutical Preparations Plant Roots Recurrence Research Research Personnel Risk Factors Sampling Sensory Ganglia Seroprevalences Sexual Partners Sexually Transmitted Diseases Simplexvirus Skin Surface Swab T-Lymphocyte Testing Therapeutic Time Training Programs Travel Ulcer Universities Viral Virus Virus Diseases Virus Shedding Washington Woman afferent nerve career cohort experience genital herpes latent infection novel prevent programs research study response transmission process valacyclovir

项目摘要

DESCRIPTION (provided by applicant): Dr. Christine Johnston completed Infectious Diseases fellowship and an MPH degree in epidemiology at the University of Washington in 2007. This proposal describes a 5 year training program which will allow her to develop an independent academic career in clinical research studying genital herpes simplex virus-2 (HSV-2) infection, and will build on prior experiences studying host-viral interactions and herpesvirus replication at mucosal surfaces. Drs. Anna Wald and Lawrence Corey are internationally renowned leaders in clinical HSV-2 research and are co-mentors for this award. HSV-2 is the most prevalent sexually transmitted infection 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. Preliminary data indicate that subclinical shedding may occur simultaneously at several genital locations and that "short bursts" of HSV-2 replication occur in the presence of suppressive antiviral therapy. These data suggest that 1) we may have overestimated the degree of suppression provided by antiviral therapy and 2) genital mucosal responses are essential for control of HSV-2 replication. To evaluate "short bursts" of shedding, a cohort of 50 HSV-2 seropositive persons on suppressive antiviral therapy will obtain genital swabs 4 times per day for 60 days. The rate and duration of HSV-2 shedding episodes will be compared with rates off therapy (Aim 1). For Aims 2 & 3,15 HSV-2 seropositive people not on therapy (Aim 2) and 15 persons on suppressive therapy (Aim 3) will be seen daily over a 30 day period to capture episodes of asymptomatic shedding, using a novel rapid HSV PCR test. Genital biopsies will be performed within hours of HSV-2 detection. Gene expression patterns using microarrays and HSV specific T-cell function will be evaluated. Results will be compared to biopsies obtained from the same participants in the presence of genital lesions. These studies will help us understand HSV-2 pathogenesis and the responses mediating viral clearance, which will inform therapeutic strategies to prevent the epidemic spread of HSV-2 and HIV.

描述（由申请人提供）：Christine Johnston 博士于 2007 年在华盛顿大学完成了传染病研究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，该计划将使她能够在临床研究领域发展独立的学术职业生涯研究生殖器单纯疱疹病毒 2 (HSV-2) 感染，并将建立在研究宿主病毒相互作用和粘膜表面疱疹病毒复制的先前经验基础上。博士。 Anna Wald 和 Lawrence Corey 是 HSV-2 临床研究领域国际知名的领导者，也是该奖项的共同导师。 HSV-2 是全球最流行的性传播感染，并已成为感染和传播 HIV 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。初步数据表明，亚临床脱落可能同时发生在多个生殖器部位，并且在抑制性抗病毒治疗的情况下会发生 HSV-2 复制的“短爆发”。这些数据表明：1）我们可能高估了抗病毒治疗的抑制程度；2）生殖器粘膜反应对于控制 HSV-2 复制至关重要。为了评估“短暂爆发”的脱落情况，一组接受抑制性抗病毒治疗的 50 名 HSV-2 血清阳性患者将在 60 天内每天采集 4 次生殖器拭子。 HSV-2 脱落事件的发生率和持续时间将与停止治疗的发生率进行比较（目标 1）。对于目标 2 和 3，将在 30 天内每天对 15 名未接受治疗的 HSV-2 血清阳性患者（目标 2）和 15 名接受抑制治疗的患者（目标 3）进行观察，以捕获无症状排毒事件，使用新型快速 HSV PCR测试。生殖器活检将在 HSV-2 检测后数小时内进行。将使用微阵列和 HSV 特异性 T 细胞功能评估基因表达模式。结果将与从存在生殖器病变的相同参与者获得的活检进行比较。这些研究将帮助我们了解 HSV-2 发病机制和介导病毒清除的反应，从而为预防 HSV-2 和 HIV 流行性传播的治疗策略提供信息。