Clinical Research in HSV Infections

描述(由申请者提供)：这个更新的K24职业生涯中期研究人员奖的首要目标是在高质量的以患者为中心的临床病毒学研究中培养有前途的初级研究人员，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，其中包括几个获得K23奖项的人，并发表了55篇由导师首次撰写的手稿。此外，沃尔德博士还扩大了她的研究组合，并扩大了她的指导活动的范围。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。 我们的小组已经证明HSV-2在生殖道中频繁地重新激活，这些上皮性感染通过宿主免疫迅速被清除。通过生殖器粘膜的活检，我们发现HSV-2感染与密集和持续的免疫细胞渗透有关，其中许多细胞携带HIV进入受体。受资助的项目有这些特定的目标：1)根据性别和免疫抑制程度确定迅速清除(&lt；6小时)粘膜HSV-2感染的频率；2)确定粘膜HSV重新激活与重新激活解剖部位生殖器皮肤局部渗入HSV-2特异性CD8+T细胞的清除率。我们假设脱落片段的清除和下一次重新激活的时间将与特定解剖部位的CD8+细胞密度相关。 新提出的项目包括研究生殖器HSV-1以及HSV-2与异常阴道微生物区系之间的相互作用。近十年来，美国生殖器疱疹的主要原因已从单纯疱疹病毒2型转变为单纯疱疹病毒1型。然而，关于这种感染的自然史研究还很匮乏。具体目标3将通过以下方式解决这些差距：a)确定新感染(6个月)和确诊(2年)生殖器HSV-1感染的男性和女性迅速清除(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%的性伴会有HSV-1从生殖道脱落，从而表明HSV-1在生殖器间传播的可能性。 流行病学研究表明HSV和细菌性阴道病之间存在相互作用；我们将把这些初步观察扩展到临床和机制研究。具体目标4将评估阴道微生物区系对HSV脱落的影响以及HSV抑制对阴道微生物区系的影响。我们假设这两种情况将会相互影响，并且这种影响将由可溶性炎症介质，如分泌性白细胞蛋白酶抑制物、人中性粒细胞多肽1-3和乳铁蛋白等所介导。 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中心的研究和为临床病毒学研究生涯做准备的机会。

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.