Clinical Research in HSV Infections

HSV 感染的临床研究

• 批准号: 8190026
• 负责人: Anna Wald
• 金额: $ 18.29万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-15 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8190026
• 关键词: Acyclovir; Address; Adverse effects; Affect; Africa South of the Sahara; Anatomic Sites; Antiviral Agents; Antiviral Therapy; Area; Bacterial Vaginosis; Benign; Biopsy; CCR5 gene; CD209 gene; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Chronic; Clinical; Clinical Investigator; Clinical Research; Clinical Trials; Clinical Virology; Complex; Congenital herpes simplex; Counseling; Dendritic Cells; Dermal; Developed Countries; Diagnostic; Disease; Epidemiologic Studies; Epidemiology; Epithelial; Failure; Fostering; Frequencies; Funding; Gender; Genital system; Goals; Grant; HIV; Health; Herpesvirus 1; Human; Human Herpesvirus 2; IL3RA gene; IL8 gene; Immune; Immune response; Immunity; Immunocompetent; Immunocompromised Host; Immunologics; Immunosuppression; Infection; Inflammation Mediators; Knowledge; Lactoferrin; Maintenance; Manuscripts; Measures; Mediating; Mentored Patient-Oriented Research Career Development Award; Mentors; Metabolic Clearance Rate; Midcareer Investigator Award in Patient-Oriented Research; Morbidity - disease rate; Mucous Membrane; Muramidase; Natural History; Natural Immunity; Nerve Endings; Outcome; Patients; Persons; Pharmaceutical Preparations; Physicians; Population; Preparation; Publishing; Recurrence; Research; Research Personnel; Risk; Series; Sexual Partners; Simplexvirus; Site; Skin; Supervision; T-Lymphocyte; Therapeutic; Time; Training; Vaccines; Vagina; Virus; Virus Diseases; Virus Shedding; Woman; antileukoprotease; career; chemokine receptor; density; epidemiologic data; genital herpes; genital infection; human SLPI protein; human neutrophil peptide 1; improved; insight; interest; men; mortality; next generation; novel; pathogen; patient oriented research; receptor; research study; transmission process

DESCRIPTION (provided by applicant): The overarching goal of this Renewal K24 Midcareer Investigator Award in Patient-Oriented Research is to foster training of promising junior investigators in high quality Patient-Oriented Research in clinical virology, with a focus on HSV infections. During the first cycle of K24 funding, the PI achieved her original goals, increased the number of clinical investigators under her supervision, including several with K23 awards, and published 55 manuscripts first-authored by mentees. Additionally, Dr. Wald has expanded her research portfolio, and broadened the scope of her mentoring activities. Ongoing projects include translational, clinical, therapeutic, epidemiologic, and preventative research, as well as clinical trials of drugs and vaccines. Our group has shown that HSV-2 reactivates frequently in the genital tract and that these epithelial infections are rapidly cleared by host immunity. Using biopsies of genital mucosa, we have shown that HSV-2 infection is associated with a dense and persistent infiltrate of immune cells, many bearing HIV entry receptors. The funded projects have these Specific Aims: 1) To determine the frequency of rapidly cleared (<6 hrs) mucosal HSV-2 infections by gender and degree of immunosuppression; 2) To define the clearance rate of mucosal HSV reactivation in relation to locally infiltrating HSV-2-specific CD8+ T cells in genital skin at the anatomic site of reactivation. We hypothesize that the clearance of the shedding episode and time to next reactivation will correlate with the density of CD8+ cells at specific anatomic sites. The newly proposed projects include studies of genital HSV-1 and of interactions between HSV-2 and abnormal vaginal microbiota. Recent decade has seen a shift from HSV-2 to HSV-1 as the predominant cause of genital herpes in US. Yet natural history studies of this infection are lacking. The Specific Aim 3 will address these gaps by: A) determining the frequency of rapidly cleared (<6 hrs) mucosal HSV-1 infections in men and women with newly acquired (<6 months) and established (>2 years) genital HSV-1 infections; 2) evaluating the site of HSV infection in persons who transmitted genital HSV-1 infection to their partners. We hypothesize that > 50% of sex partners will have HSV-1 shedding from the genital tract, thus indicating the possibility of genital-to-genital HSV-1 transmission. Epidemiologic studies suggest an interaction between HSV and bacterial vaginosis; we will extend these pilot observations into clinical and mechanistic studies. Specific aim 4 will evaluate the effect of vaginal microbiota on HSV shedding and the effect of HSV suppression on vaginal microbiota. We hypothesize that these 2 conditions will have an adverse effect on each other, and that the effect will be mediated by soluble mediators of inflammation, such as secretory leukocyte protease inhibitor, human neutrophil peptides 1-3 and lactoferrin,. These carefully selected projects provide opportunities for training junior clinical investigators in high-quality Patient-Oriented Research and preparations for an investigative career in clinical virology. PUBLIC HEALTH RELEVANCE (provided by applicant): This application supports ongoing training of the next generation of physician investigators in studies in clinical virology, in particular in genital herpes, an infection that affects about 20% of US population. This research aims to investigate the relationship between the virus and the immune response in the genital tract, increase our knowledge about genital infections caused by herpes simplex virus type 1 as well as about interaction between genital herpes and bacterial vaginosis, another common condition of women.

描述（由申请人提供）：本次以患者为导向的研究更新 K24 职业生涯中期研究者奖的总体目标是促进对有前途的初级研究者进行临床病毒学高质量以患者为导向的研究的培训，重点是 HSV 感染。在 K24 资助的第一个周期中，PI 实现了她最初的目标，增加了她监督下的临床研究人员的数量，其中包括几位获得 K23 奖项的人，并发表了 55 篇由学员第一作者的手稿。此外，沃尔德博士还扩大了她的研究范围，并扩大了她指导活动的范围。正在进行的项目包括转化、临床、治疗、流行病学和预防研究，以及药物和疫苗的临床试验。 我们的研究小组已经证明，HSV-2 在生殖道中频繁重新激活，并且这些上皮感染会被宿主免疫迅速清除。通过生殖器粘膜活检，我们发现 HSV-2 感染与免疫细胞密集且持续的浸润有关，其中许多免疫细胞携带 HIV 进入受体。资助项目有以下具体目标： 1) 按性别和免疫抑制程度确定快速清除（<6 小时）粘膜 HSV-2 感染的频率； 2) 确定粘膜 HSV 再激活的清除率与再激活解剖部位生殖器皮肤中局部浸润的 HSV-2 特异性 CD8+ T 细胞的关系。我们假设脱落事件的清除和下次重新激活的时间将与特定解剖部位的 CD8+ 细胞的密度相关。 新提出的项目包括生殖器 HSV-1 以及 HSV-2 与异常阴道微生物群之间相互作用的研究。近十年来，美国生殖器疱疹的主要原因已从 HSV-2 转变为 HSV-1。然而，缺乏对这种感染的自然史研究。具体目标 3 将通过以下方式解决这些差距：A) 确定新获得（<6 个月）和已确定（>2 年）生殖器 HSV-1 感染的男性和女性中快速清除（<6 小时）粘膜 HSV-1 感染的频率； 2) 评估将生殖器 HSV-1 感染传播给其伴侣的人的 HSV 感染部位。我们假设 > 50% 的性伴侣会从生殖道排出 HSV-1，从而表明生殖器之间存在 HSV-1 传播的可能性。 流行病学研究表明 HSV 和细菌性阴道病之间存在相互作用；我们将把这些试点观察扩展到临床和机制研究。具体目标 4 将评估阴道微生物群对 HSV 脱落的影响以及 HSV 抑制对阴道微生物群的影响。我们假设这两种情况会相互产生不利影响，并且这种影响将由可溶性炎症介质介导，例如分泌性白细胞蛋白酶抑制剂、人中性粒细胞肽1-3和乳铁蛋白。 这些精心挑选的项目为培训初级临床研究人员提供了高质量的以患者为导向的研究的机会，并为临床病毒学的研究生涯做好准备。 公共卫生相关性（由申请人提供）：本申请支持对下一代临床病毒学研究医师研究人员进行持续培训，特别是生殖器疱疹（一种影响约 20% 的美国人口的感染）。本研究旨在调查病毒与生殖道免疫反应之间的关系，增加我们对 1 型单纯疱疹病毒引起的生殖器感染以及生殖器疱疹与细菌性阴道病（女性另一种常见病）之间相互作用的了解。