Ocular HSV-1: Preventing Recurrent Corneal Disease

描述(由申请人提供)：复发性单纯疱疹病毒1型(HSV-1)感染是由于感染性因素导致的角膜失明的主要原因。由于美国超过80%的成年人患有潜伏的HSV，此时预防潜伏感染患者复发的治疗性治疗可能比预防感染的预防性治疗更有益。最近，一种特殊形式的高强度磁离子脉冲(HIMII)似乎可以防止三个有严重口腔HSV-1复发病史的人未来的HSV-1复发。非侵入性HIMII可在体内诱导神经元产生电流，从而影响神经元的活动。由于神经元的HSV-1潜伏期至少部分由神经元调节，因此HIMII可能会影响HSV-1潜伏期的重新激活周期。除了防止临床复发，HIMII治疗还降低了所有三个受试者的抗HSV血清抗体效价，从治疗前的很高水平下降到治疗一年后的可检测水平以下。由于我们最近表明，抗体滴度的下降表明再激活大大减少，这一发现反对简单的安慰剂效应导致临床复发的减少。我们假设，高强度磁离子脉冲(HIMII)治疗可以显著减少潜伏感染HSV-I的兔眼的自发复活。 我们的具体目标包括：(1)证实HIMII治疗将显著减少兔眼模型的自发再激活。病毒脱落、复发性眼病和抗HSV-1抗体效价都将进行检查。(2)通过减少兔三叉神经节中潜伏的HSV-1的数量来验证HIMII治疗减少自发激活的假说。在治疗后的不同时间，将使用分子技术来确定潜伏期的数量，包括原位杂交和原位PCR来确定潜伏感染神经元的相对数量，以及激光捕获显微解剖和实时荧光定量聚合酶链式反应来确定单个神经元中潜伏病毒的数量。(3)确定最佳抑制HSV-1自发再激活所需的最佳HIMII治疗方案。

DESCRIPTION (provided by applicant): Recurrent herpes simplex virus type 1 (HSV-1) infection is a major cause of corneal blindness due to an infectious agent. Since over 80% of adults in the US harbor latent HSV, at this time a therapeutic treatment to prevent recurrent disease in latently infected individuals may be even more beneficial than a prophylactic treatment to prevent acquisition. Recently, a specific form of high intensity magnetic ion impulses (HIMII) appeared to prevent future HSV-1 recurrences in three of three individuals with a history of severe oral HSV-1 recurrences. Noninvasive HIMII can induce electrical current in neurons in vivo thus affecting their activity. Since neuronal HSV-1 latency is regulated at least in part by the neuron, it is logical that HIMII could affect the HSV-1 latency reactivation cycle. In addition to preventing clinical recurrences, the HIMII treatment also reduced anti-HSV serum antibody titers in all three subjects, from very high prior to treatment to below detectable levels one year after treatment. Since we recently showed that decreasing antibody titers are indicative of greatly reduced reactivation this finding argues against a simple placebo effect being responsible for the reduced clinical recurrences. We hypothesize that treatment with high intensity magnetic ion impulses (HIMII) can significantly decrease spontaneous reactivation in eyes of rabbits latently infected with HSV-I. Our Specific Aims include: (1)Confirm that HIMII treatment will significantly reduce spontaneous reactivation in the rabbit eye model. Virus shedding, recurrent eye disease, and anti-HSV-1 antibody titers will all be examined. (2)Test the hypothesis that HIMII treatment decreases spontaneous reactivation by decreasing the amount of latent HSV-1 in rabbit trigeminal ganglia. At various times after treatment the amount of latency will be determined using molecular techniques including in situ hybridization and in situ PCR to determine the relative number of latently infected neurons, and laser capture microdissection followed by real time PCR to determine the amount of latent virus in individual neurons. (3) Determine the optimal HIMII treatment regimen required for optimal suppression of HSV-1 spontaneous reactivation.