Ocular HSV-Latency, Reactivation, and Recurrence

描述（由申请人提供）：单纯疱疹病毒（HSV）是工业化国家传染性失明的主要原因。在美国，每年治疗30万例。眼部HSV引起自限性上皮角膜炎、睑缘炎、结膜炎、基质角膜炎和最具破坏性的疾病坏死性疱疹性基质角膜炎（HSK）。HSK是最难管理的;大约一半的患者对联合化疗没有反应，并且会有明显的视力丧失或失明。HSV是一种神经营养性病毒，其特征在于其能够在神经元中建立终身潜伏期并在外周部位重新激活，从而引起复发性疾病。眼复发引起显著的角膜瘢痕形成，导致HSK。我们的建议将检查低和高HSV-1表型再激活剂之间的关系，在小鼠模型高度敏感的眼部发病机制。载脂蛋白E（ApoE）的e4等位基因是眼部疱疹的危险因素。我们将证明不同表型（株）的HSV在e4基因敲入小鼠中具有不同的眼部发病机制，该基因敲入小鼠是通过将人ApoE基因插入去除小鼠ApoE基因的转基因小鼠中而产生的转基因小鼠株。我们将评估两种基于ApoE模拟受体的肽，其在联合治疗中分别表现出抗病毒和抗疱疹活性，以治疗e4小鼠中由HSV-1感染引起的严重眼部发病机制。我们假设，我们的研究使用两种ApoE肽将记录减少眼部发病机制和氧化损伤的神经元和表观遗传控制，这是受这种疗法。为此，我们计划遵循这些特定目的：特定目的1：检验以下假设：当感染HSV-1的高表型和低表型再活化株时，e4小鼠的眼部发病机制将发生显著差异。具体目标二：为了检验以下假设：与潜伏感染低表型再激活因子的小鼠相比，当诱导潜伏感染高表型再激活因子的ApoE e4小鼠再激活时，将发生更多的发病机制。具体目标3：检验以下假设：使用两种独特的ApoE肽治疗将成功抑制ApoE e4小鼠中高表型再激活因子诱导HSV-1再激活。这些研究如果成功，将证明1）对比HSV-1表型菌株在眼疱疹中的作用，2）使用具有高表型再活化剂并给予HSV-1诱导刺激的潜伏小鼠的e4等位基因携带者的易感性和增加的发病机制，和3）两种ApoE肽可以抑制HSV- 1再活化和眼发病机制，甚至在给予HSV-1诱导剂的高度易感的e4小鼠中也是如此。这些药理学研究将为眼部疱疹患者提供新的联合治疗的可能性，并可能为其他HSV疾病，如脑炎和生殖器疱疹。这些研究涉及转化研究、表观遗传学和眼部发病机制，符合2006年12月国家眼科和视力研究计划的研究目标。公共卫生相关性：单纯疱疹病毒（HSV）是所有工业化国家传染性非创伤性失明的主要原因，在美国每年治疗超过30万例。虽然有治疗方法，但一些患者对目前的治疗仍然具有强烈的耐药性，因此我们的研究针对特定的人类基因，载脂蛋白E（ApoE）的e4等位基因，该基因与眼部HSV- 1的发病机制有关。使用两种基于受体的ApoE模拟肽，其表现出有效的抗病毒和抗炎活性，并抑制该基因，作为眼部和其他HSV相关疾病的新疗法具有很大的前景。

DESCRIPTION (provided by applicant): Herpes simplex virus (HSV) is the leading cause of infectious blindness in the industrialized nations. In the USA, 300,000 cases are treated yearly. Ocular HSV causes a self-limiting epithelial keratitis, blepharitis, con- junctivitis, stromal keratitis, and the most damaging disease, necrotizing herpetic stromal keratitis (HSK). HSK is the most difficult to manage; about half of the patients do not respond to combination chemotherapy and will have significant loss of vision or blindness. HSV is a neurotrophic virus characterized by its ability to establish lifelong latency in neurons and to reactivate at peripheral sites, causing recurrent disease. The ocular recur- rences cause significant corneal scarring, leading to HSK. Our proposal will examine the relationship between low and high HSV-1 phenotypic reactivators in a mouse model highly susceptible to ocular pathogenesis. The e4 allele of Apolipoprotein E (ApoE) is a risk factor for ocular herpes. We will demonstrate that different phenotypes (strains) of HSV have different ocular pathogenesis in e4 knock-in mice, a transgenic mouse strain created by insertion of the human ApoE gene into a trans- genic mouse from which the mouse ApoE gene was removed. We will evaluate two ApoE mimetic receptor- based peptides that separately exhibit anti-viral and anti-herpetic activity in a combination therapy to treat the severe ocular pathogenesis resulting from HSV-1 infection in e4 mice. We hypothesize that our investigation using the two ApoE peptides will document a reduction in ocular pathogenesis and oxidative damage in neurons and epigenetic control that is affected by this therapy. To this end, we plan to follow these Specific Aims: Specific Aim 1: To test the hypothesis that significant differences in ocular pathogenesis will occur in e4 mice when infected with high and low phenotypic reactivating strains of HSV-1. Specific Aim 2: To test the hypothesis that more pathogenesis will occur when ApoE e4 mice latently infected with the high phenotypic reactivator are induced to reactivate than in those latently infected with the low phenotypic reactivator. Specific Aim 3: To test the hypothesis that therapy with two unique ApoE peptides will successfully inhibit the induction of HSV-1 reactivation of the high phenotypic reactivator in ApoE e4 mice. These studies, if successful, will demonstrate 1) the role of contrasting HSV-1 phenotypic strains in ocular herpes, 2) the susceptibility and increased pathogenesis of the e4 allele carrier using mice latent with a high phenotypic reactivator and given an HSV-1 induction stimulus, and 3) that two ApoE peptides can inhibit HSV- 1 reactivation and ocular pathogenesis, even in highly susceptible e4 mice that are given an HSV-1 inducer. These pharmacological studies will offer the possibility of a new combination therapy for patients with ocular herpes and possibly for other HSV diseases such as encephalitis and genital herpes. These studies involving translational research, epigenetics, and ocular pathogenesis are in accordance with the research goals of the December 2006 National Plan for Eye and Vision Research. PUBLIC HEALTH RELEVANCE: Herpes Simplex Virus (HSV) is the leading cause of infectious, non-traumatic blindness in all industrialized nations, with over 300,000 cases treated in the United States per year. While therapies are available, some patients remain strongly resistant to current treatments, thus our research targets a specific human gene, the e4 allele of apolipoprotein E (ApoE), which has been implicated in the pathogenesis of ocular HSV- 1. The use of two receptor-based ApoE mimetic peptides that exhibit potent anti-viral and anti-inflammatory activity, and which act to suppress this gene, holds great promise as a new therapy for ocular and other HSV-related diseases.