Mechanisms of Reactivation and Clearance of Mucosal HSV Infection

我们在过去2年的研究表明，HSV-2的再激活具有更快和更频繁的速度 发病和清除比以前认识到的;超过40%的所有HSV-2再激活持续<6小时; 这些短暂的再活化的特征是快速释放103至104个HSV-2拷贝 DMA粘附在粘膜表面，并伴随着宿主对病毒的快速清除。类似的模式 口唇HSV感染似乎会发生再激活。粘膜HSV的宿主清除率不同 从<0.3 log HSV DMA/小时到2 log/小时。最近的研究 原位CDS T细胞反应表明，外周中的HSV-2特异性T细胞在真皮表皮中持续存在。 连接邻接神经元末梢，宿主免疫反应可包含病毒 甚至在引起粘膜溃疡之前就复制了。 该项目旨在通过以下方法表征快速清除粘膜HSV感染的频率： 解剖部位、性别、病毒亚型（HSV-1与HSV-2）和免疫抑制程度 （免疫功能正常的患者、孕妇、接受/未接受HAART的HIV阳性患者和接受HAART后的患者） 造血干细胞移植（HSCT）。这些研究将确定快速 在这些患者人群中发生清除的发作。然后我们将招收快速和缓慢的人， 清除率纳入机制研究，以确定清除率与解剖结构之间的相关性 皮肤中HSV-2特异性CD 8 + T细胞的位置和功能特征。我们将检验这个假设， 粘膜HSV再活化的清除率将与HSV-2特异性抗体的存在呈负相关。 生殖器皮肤中的CD 8 +T细胞在重新激活的部位。确定HSV功能特征的研究- 还将对似乎参与免疫监视的2种特定细胞进行检测。此外，Pilot 研究确定增加抗HSV治疗剂量是否会消除这些粘膜HSV的短暂爆发 重新激活并提供对HSV-2的更佳抑制。HSV-2/HIV-1共感染者 人，我们将定义HSV-2再激活和HIV-1复制之间的时间动态粘膜上 使用新开发的高灵敏度HIV-1 RNA检测表面，并在连续活检中进行评估 样品中HSV-2特异性CD 8 + T细胞在HIV感染患者中HSV-2消退中的作用。我们将 测试以下假设：最小化亚临床HSV-2再活化的给药方案将产生更多的 在CD 4 T细胞计数>400个细胞/ml的艾滋病毒合并感染者中，艾滋病毒RNA持续减少。 项目1旨在确定和开发控制HSV-2感染的新策略， 可以为风险群体采取改进的医疗和公共卫生管理战略。

Our studies in the last 2 years have shown that HSV-2 reactivation has both a more rapid and frequent pace of onset and clearance than previously appreciated; more than 40% of all HSV-2 reactivations last <6 hours; these short episodes of reactivation are characterized by the rapid release of 103 to 104 copies of HSV-2 DMA onto mucosal surfaces and accompanied by the rapid clearance of virus by the host. A similar pattern of reactivation appears to occur for oral-labial HSV infection. Host clearance of mucosal HSV varies considerably between individual from <0.3 logs of HSV DMA/hour to 2 logs/hour. Recent studies mapping CDS T cell responses in situ indicate that HSV-2 specific T cells in the periphery persist at the dermalepidermal junction contiguous to neuronal endings and that the host immune responses can contain viral replication even before it causes mucosal ulcerations. This project is directed at characterizing the frequency of rapidly cleared mucosal HSV infections by anatomic site, gender, viral subtype (HSV-1 versus HSV-2), and degree of immunosuppression (immunocompetent patients, pregnant women, HIV positive patients on/off HAART, and patients post hematopoietic stem cell transplantation (HSCT). These studies will define the frequency in which rapidly cleared episodes occur in these patient populations. We will then enroll persons with rapid and slow clearance rates into mechanistic studies to define the association between clearance rate and the anatomic site and functional characteristics of HSV-2 specific CD8+ T-cells in skin. We will test the hypothesis that clearance rates of mucosal HSV reactivation will be inversely correlated with the presence of HSV-2 specific CD8+T cells in genital skin at the site of reactivation. Studies to define the functional characteristics of HSV- 2 specific cells that appear to participate in immune surveillance will also be performed. In addition, pilot studies to define if increasing doses of anti-HSV therapy will eliminate these short bursts of mucosal HSV reactivation and provide more optimal suppression of HSV-2 are proposed. Among HSV-2/HIV-1 co infected persons, we will define the temporal dynamics between HSV-2 reactivation and HIV-1 replication on mucosal surfaces using a newly developed, highly sensitive HIV-1 RNA assay and evaluate in sequential biopsy samples the role HSV-2 specific CD8+ T-cells play in resolution of HSV-2 in the HIV infected patient. We will test the hypothesis that dosing regimens that minimize sub clinical HSV-2 reactivation will produce more sustained reduction in HIV RNA among HIV co-infected persons with CD4 T-cell counts >400 cells/ml. Project 1 is designed to define and develop new strategies for controlling HSV-2 infection and identify high risk groups for which improved medical and public health management strategies can be initiated.