Persistence of CNS T. pallidum in HIV Infection

描述(由申请者提供)：美国和欧洲目前在与男性发生性行为的男性中爆发梅毒，其中许多人是艾滋病毒感染者。这一点特别令人担忧，因为神经梅毒可能在艾滋病毒感染者中更为常见。我们的神经梅毒研究始于1996年。我们最初提案的总体目标是测试HIV感染损害梅毒螺旋体从脑脊液(CSF)中清除的假设。我们的研究结果支持了这一假设。具体地说，艾滋病毒介导的免疫抑制更明显的个人更有可能患有神经梅毒，在治疗神经梅毒后，脑脊液-性病研究实验室(VDRL)反应正常化的可能性大大降低，特别是那些患有晚期免疫抑制的艾滋病毒感染者。在我们的竞争更新中，我们专注于预测神经梅毒及其治疗反应。在过去的15个月里，我们在实现我们先前的目标方面取得了实质性进展。我们已经证明，脑脊液细胞表型可以用来支持HIV感染患者神经梅毒的诊断，有更多的初步数据支持血液中更大的梅毒遗传多样性与神经梅毒之间的关联，并已经确定了神经梅毒治疗反应的新标记物。截至2003年12月1日，我们从470名梅毒患者中招募并获取了脑脊液，其中91人在神经梅毒治疗后至少进行了一次腰椎穿刺术。大约四分之三的受试者也感染了艾滋病毒。在这个竞争性的更新应用中，我们继续关注关于神经梅毒和艾滋病毒的临床和病理上的重要问题。具体目标是：1)确定预测艾滋病毒感染者和非感染者患神经梅毒的高可能性的方法；2)区分梅毒螺旋体感染引起的脑脊液细胞增多症和艾滋病毒感染引起的脑脊液细胞增多症；3)确定与艾滋病毒感染者和非感染者神经梅毒治疗反应相关的因素。我们正在进行的研究是几十年来对神经梅毒进行的最大规模的调查，也是唯一一项具有足够的力量来研究伴随的HIV感染对神经梅毒的发展的影响以及HIV感染者和非感染者对神经梅毒治疗的反应的研究。

DESCRIPTION (provided by applicant): The US and Europe are currently experiencing outbreaks of syphilis in men who have sex with men, many of whom are HIV-infected. This is of particular concern because neurosyphilis may be more common in HIV-infected individuals. Our neurosyphilis studies began in 1996. The overall goal of our original proposal was to test the hypothesis that HIV infection impairs clearance of Treponema pallidum from the cerebrospinal fluid (CSF). The results of our studies support this hypothesis. Specifically, individuals with more pronounced HIV-mediated immunosuppression are more likely to have neurosyphilis, and normalization of CSF-Venereal Disease Research Laboratory (VDRL) reactivity after treatment for neurosyphilis is significantly less likely in HIV-infected individuals, particularly those with advanced immunosuppression. In our competing renewal, we focused on predicting neurosyphilis and its treatment response. In the last 15 months, we have made substantial progress in addressing our previous Aims. We have shown that the CSF cellular phenotype can be used to support a diagnosis of neurosyphilis in HIV-infected patients, have additional preliminary data in support of the association between greater genetic diversity of blood T. pallidum and neurosyphilis, and have identified new markers of neurosyphilis treatment response. As of Dec 1,2003, we have enrolled and obtained CSF from 470 subjects with syphilis, and 91 have had at least one follow-up lumbar puncture after neurosyphilis treatment. Approximately three-quarters of our subjects are also HIV-infected. In this competing renewal application, we continue to focus on clinically and pathogenetically important questions regarding neurosyphilis and HIV. The Specific Aims are: 1) Identify measures that predict a high likelihood of neurosyphilis in HIV-infected and -uninfected individuals; 2) Distinguish CSF pleocytosis due to T. pallidum infection from CSF pleocytosis due to HIV infection; 3) Determine factors associated with response to neurosyphilis therapy in HIV-infected and -uninfected individuals. Our ongoing study is the largest investigation of neurosyphilis in many decades, and is the only study with sufficient power to address the effect of concomitant HIV infection on development of neurosyphilis and the response to neurosyphilis therapy in both HIV-infected and -uninfected individuals.