Persistence of CNS T. pallidum in HIV Infection

描述(由申请人提供)：我们最初提案的总体目标是测试伴随HIV-1感染会损害梅毒螺旋体从脑脊液中清除的假设。我们在第一个资助期取得的进展支持了我们的假设。具体地说，HIV-1介导的免疫抑制更明显的人更有可能患有神经梅毒，在HIV-1感染的人中，治疗神经梅毒后脑脊液白细胞计数和血清RPR的正常化速度较慢且不完全。很少有研究指出伴随的HIV-1对梅毒螺旋体感染中枢神经系统的影响。到目前为止，在我们的研究中，我们从348名患有所有阶段的梅毒的受试者中招募并获取了脑脊液。大约四分之三的受试者也感染了HIV-1。到目前为止，53名受试者至少进行了一次上腰椎后续穿刺术。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研究，也是唯一一项有足够能力解决HIV-1感染和未感染的人中同时感染HIV-1对神经梅毒的影响和神经梅毒治疗反应的研究。在这个相互竞争的续订申请中，我们将重点放在三个临床重要问题上。这些问题和每个问题要检验的主要假设是：1)哪些感染和未感染HIV-1的梅毒患者应该接受腰椎穿刺术，以评估神经梅毒的可能性？我们假设，血液中梅毒螺旋体浓度较高的人，血液中具有特定菌株类型的人，以及那些血液中梅毒螺旋体菌株具有更大多样性的人，将更有可能患上神经梅毒。我们将在特定的目标1中检验这些假设；2)如何区分感染梅毒螺旋体引起的脑脊液细胞增多症和由于HIV-1感染引起的脑脊液细胞增多症？我们推测，脑脊液细胞表型和脑脊液淋巴细胞产生梅毒螺旋体特异性抗体可以区分梅毒螺旋体诱导的脑脊液细胞增殖和HIV-1诱导的脑脊液细胞增殖。我们将在特定的目标2中检验这些假设；以及3)哪些因素决定了HIV-1感染和未感染的神经梅毒患者的治疗反应？我们推测，治疗的快速和完全反应将与脑脊液梅毒螺旋体浓度和脑脊液梅毒螺旋体菌株类型有关。我们将在特定的目标3中检验这些假设。本申请中提出的研究与HIV-1和梅毒患者的护理直接相关，并最终将提高我们诊断和治疗神经梅毒的能力。

DESCRIPTION (provided by applicant): The overall goal of our original proposal was to test the hypothesis that concomitant HIV-1 infection impairs clearance of Treponema pallidum from the CSF. The progress that we have made in the first funding period supports our hypothesis. Specifically, individuals with more pronounced HIV-1-mediated immunosuppression are more likely to have neurosyphillis, and normalization of CSF WBC count and serum RPR after treatment for neurosyphilis is slower and less complete in HIV-1-infected individuals. Few studies have addressed the influence of concomitant HIV-1 on CNS infection by T. pallidum. In our study to date, we have enrolled and obtained CSF from 348 subjects with all stages of syphilis. Approximately three-quarters of our subjects are also HIV-1-infected. To date, 53 subjects have had at least one follow-uplumbar puncture. Our ongoing study represents the largest investigation of neurosyphilis in many decades, and is the only study with sufficient power to address the effect of concurrent HIV-1-infection on development of neurosyphilis and the response to neurosyphilis therapy in HIV-1-infected and -uninfected individuals. In this competing renewal application, we focus on three clinically important questions. These questions and the principal hypotheses to be tested for each are: 1) Which HIV-1-infected and -uninfected patients with syphilis should undergo lumbar puncture to evaluate the possibility of neurosyphilis? We hypothesize that individuals with higher concentrations of T. pallidum in blood, those with particular strain types in blood and those with greater diversity of blood T. pallidum strains will be more likely to have neurosyphilis. We will test these hypotheses in Specific Aim 1; 2) How can CSF pleocytosis due to infection with T. pallidum be distinguished from CSF pleocytosis due to HIV-1 infection? We hypothesize that the CSF cellular phenotype and that production of T. pallidum-specific antibody by CSF lymphocytes will distinguish T. pallidum-induced from HIV-1-induced CSF pleocytosis. We will test these hypotheses in Specific Aim 2; and 3) What factors determine response to therapy in HIV-1-infected and -uninfected patients with neurosyphilis? We hypothesize that rapidity and completeness of response to treatment will be related to CSF T. pallidum concentration and to CSF T. pallidum strain type. We will test these hypotheses in Specific Aim 3. The studies proposed in this application are directly relevant to the care of patients with HIV-1 and with syphilis and will ultimately improve our ability to diagnose and treat neurosyphilis.