Clinical Research in HSV Infections

描述（由申请人提供）：在以患者为导向的研究中，这一更新K24中期职业研究者奖的总体目标是促进对有前途的初级研究者进行高质量的以患者为导向的临床病毒学研究的培训，重点是HSV感染。在K24资助的第一个周期，PI实现了她的最初目标，增加了她监督下的临床研究者的数量，包括几个K23奖项，并发表了55篇由学员首次撰写的手稿。此外，Wald博士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。 我们的研究小组已经表明，HSV-2在生殖道中经常重新激活，并且这些上皮感染被宿主免疫迅速清除。通过对生殖器粘膜进行活检，我们发现HSV-2感染与免疫细胞的密集和持续浸润有关，其中许多免疫细胞带有HIV进入受体。资助的项目具有以下具体目标：1）确定按性别和免疫抑制程度快速清除（<6小时）粘膜HSV-2感染的频率; 2）确定粘膜HSV再活化与生殖器皮肤中再活化解剖部位局部浸润HSV-2特异性CD 8 + T细胞相关的清除率。我们假设脱落事件的清除和下一次再激活的时间与特定解剖部位的CD 8+细胞密度相关。 新提出的项目包括生殖器HSV-1和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病因已从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%的性伴侣会有HSV-1从生殖道脱落，因此表明生殖器间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将相互产生不良影响，并且这种影响将由可溶性炎症介质介导，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中心的研究机会，并为临床病毒学的研究生涯做好了准备。

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.