Role of lymphoid DCs in HSV-1 latency

描述（由申请人提供）：1型单纯疱疹病毒感染的标志是在感染者的神经节中建立潜伏期。在潜伏感染者的生命中，病毒偶尔会重新激活，传播回眼睛并引起复发性疾病。事实上，角膜瘢痕（CS）也被称为疱疹基质角膜炎（HSK）的一个主要原因是由HSV-1在潜伏期再激活后引起的瘢痕。减少感染小鼠三叉神经节潜伏期，减少其复发性感染和视力丧失的最有效方法是减少感染小鼠三叉神经节潜伏期。我们已经证明，在免疫小鼠中，dc的消耗显著减少了复发性HSV-1感染。潜伏期和复发率的增加与CD11c+CD8¿+ dc有关。我们之前的研究支持这样一个概念，即将dc群体从CD11c+CD8¿+转移到CD11c+CD8¿- dc将减少潜伏感染小鼠的潜伏期建立和随后的复发。因此，由于与复发性眼部感染相关的问题，预防和/或减少潜伏期的建立应成为针对眼部HSV-1的预防性免疫策略的主要目标。因此，基于我们已发表的研究和初步研究，我们将使用DCs刺激因子来转移DCs群体，以减少T细胞衰竭，从而在眼感染小鼠的tg中建立/维持潜伏期。我们提出：目的：验证将dc推向髓系相关（CD11c+CD8¿-）和远离淋巴系相关（CD11c+CD8¿+）的假设，通过减少感染小鼠三叉神经节中的T细胞耗竭来减少感染小鼠的潜伏期。我们发表的研究表明，CD11c+CD8¿+ dc参与了眼感染小鼠TGs潜伏期的增强。此外，我们的初步研究表明，CD11c+CD8¿+ dc参与T细胞耗竭，这种T细胞耗竭参与潜伏期的增加。我们将测试：(a)与用GM-CSF和gD治疗的小鼠相比，聚乙二醇化GM-CSF与gD共同给药是否会增强骨髓相关的dc，并进一步减少免疫小鼠的潜伏期，从而减少T细胞衰竭；(b)与聚乙二醇- gm - csf类似，用激动剂Ab激活淋巴毒素受体（LT - r）将驱动CD11c+CD8 -的扩增，并减少潜伏感染小鼠TGs中的潜伏期和T细胞衰竭。这些研究的结果将确定通过使用免疫刺激剂进一步刺激CD11c+CD8¿- dc以提高DNA免疫对抗HSV-1潜伏期的效果的重要性。这些疫苗策略的长期效果也将被表征，以确定是否会引发长期的CD8+ T细胞反应。

DESCRIPTION (provided by applicant): A hallmark of infection with HSV-1 is establishment of latency in ganglia of the infected individual. During the life of the latently infected individual,the virus can occasionally reactivate, travel back to the eye and cause recurrent disease. Indeed, a major cause of corneal scarring (CS) also know as herpes stromal keratitis (HSK) is the scarring induced by HSV-1 following reactivation from latency. The most efficient way to decrease latency and thus subsequent recurrent infections and loss of vision is to reduce latency in trigeminal ganglia of infected mice. We have shown that recurrent HSV-1 infection was reduced significantly by depletion of DCs in immunized mice. The increase of latency and recurrences was associated with CD11c+CD8¿+ DCs. Our previous studies support the concept that shifting the DCs population from CD11c+CD8¿+ to CD11c+CD8¿- DCs will reduce establishment of latency and the subsequent recurrences in latently infected mice. Consequently, because of the problems associated with recurrent ocular infection, preventing and/or reducing establishment of latency should be a major goal of a prophylactic immunization strategy against ocular HSV-1. Thus, based on our published and Preliminary Studies, we will use DCs stimulatory factors to shift the DCs population in order to reduce T cell exhaustion and consequently, the establishment/maintenance of latency in the TGs of ocularly infected mice. We propose to: Aim: Test the hypothesis that pushing DCs toward myeloid-related (CD11c+CD8¿-) and away from lymphoid-related (CD11c+CD8¿+) will reduce latency in infected mice by decreasing T cell exhaustion in trigeminal ganglia of infected mice. Our published studies have shown that CD11c+CD8¿+ DCs are involved in the enhancement of latency in the TGs of ocularly infected mice. In addition, our preliminary studies suggest that CD11c+CD8¿+ DCs are involved in exhaustion of T cells and this T cell exhaustion is involved in the increase of latency. We will test whether: (a) Co-administration of pegylated GM-CSF with gD will enhance myeloid-related DCs and further reduce latency in immunized mice compared with mice that treated with GM- CSF and gD by reducing T cell exhaustion; and (b) Similar to pegylated-GM-CSF, activation of the lymphotoxin ¿ receptor (LT¿r) with an agonist Ab will drive the expansion of CD11c+CD8¿- and reduce latency and decrease T cell exhaustion in TGs of latently infected mice. The results of these studies will determine the importance of further stimulating CD11c+CD8¿- DCs through the use of an immune stimulator to improve the efficacy of DNA immunization against HSV-1 latency. The long-term effects of these vaccine strategies will also be characterized to determine whether long-lived CD8+ T cell responses are elicited.