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）：该更新的K24中级护理研究者奖的总体目标是培养对临床病毒学领域高质量患者研究的有前途的初级研究人员的培训，重点是HSV感染。在K24资金的第一个周期中，PI实现了她的最初目标，增加了她在监督下的临床调查人员的数量，其中包括一些获得K23奖项的奖项，并发表了55份由受训者首次创作的手稿。此外，瓦尔德博士扩大了她的研究组合，并扩大了她的指导活动范围。正在进行的项目包括转化，临床，治疗，流行病学和预防性研究，以及药物和疫苗的临床试验。 我们的小组表明，HSV-2在生殖道中经常重新激活，并且这些上皮感染通过宿主免疫迅速清除。使用生殖器粘膜活检，我们表明HSV-2感染与免疫细胞的致密且持续的浸润有关，许多伴有HIV进入受体。资助的项目具有以下特定目的：1）确定通过性别和免疫抑制程度通过性别和程度的快速清除（<6小时）粘膜HSV-2感染的频率； 2）定义与局部浸润在生殖器皮肤中的局部浸润的HSV-2特异性CD8+ T细胞相关的粘膜HSV重新激活的清除率。我们假设脱落发作和下一个重新激活的时间的清除率将与特定解剖部位的CD8+细胞的密度相关。 新提出的项目包括对生殖器HSV-1的研究以及HSV-2和阴道菌群异常的相互作用。近十年来，从HSV-2转移到HSV-1是美国生殖器疱疹的主要原因。然而，缺乏对这种感染的自然史研究。特定目的3将通过以下方式解决这些差距：a）确定新获得（<6个月）并建立（> 2年）生殖器HSV-1感染的男性和女性中快速清除（<6 hrs）粘膜HSV-1感染的频率； 2）评估将生殖器HSV-1感染传播给伴侣的人的HSV感染部位。我们假设> 50％的性伴侣将从生殖道中脱落HSV-1，从而表明生殖器到生殖器HSV-1传播的可能性。 流行病学研究表明HSV与细菌性阴道病之间存在相互作用。我们将将这些试验观测扩展到临床和机械研究中。具体目标4将评估阴道菌群对HSV脱落的影响以及HSV抑制对阴道菌群的影响。我们假设这两种情况将彼此之间产生不利影响，并且该作用将由炎症的可溶性介体介导，例如分泌的白细胞蛋白酶抑制剂，人类嗜中性粒细胞肽1-3和乳霉菌素。 这些精心挑选的项目为培训初级临床研究人员提供了机会，以在临床病毒学领域进行调查生涯的高质量研究和准备工作。 公共卫生相关性（由申请人提供）：本申请支持对下一代医师研究人员进行临床病毒学研究的持续培训，尤其是生殖器疱疹中的培训，这种感染影响了美国人群的20％。这项研究旨在研究生殖道中病毒与免疫反应之间的关系，增加我们对1型疱疹病毒引起的生殖器感染的了解，以及对生殖器疱疹与细菌性阴道病之间的相互作用，这是女性的另一种常见状态。