Pathogenesis of leukoencephalopathies in HIV+ patients

HIV患者白质脑病的发病机制

• 批准号: 6893177
• 负责人: PASQUALE FERRANTE
• 金额: $ 24.3万
• 依托单位: FONDAZIONE DON CARLO GNOCCHI ONLUS
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6893177
• 关键词: AIDS therapy; HIV infections; Polyomavirus hominis 2; T cell receptor; antiAIDS agent; antiviral agents; chemokine receptor; clinical research; combination therapy; disease /disorder etiology; flow cytometry; genetic polymorphism; genetic susceptibility; human subject; immunocytochemistry; longitudinal human study; magnetic resonance imaging; molecular rearrangement; neuropsychological tests; opportunistic infections; pathologic process; polymerase chain reaction; progressive multifocal leukoencephalopathy; therapy adverse effect; virus load

DESCRIPTION (provided by applicant): The use of more intensive antiretroviral therapies, such as HAART, in the treatment of HIV infection has led to a marked reduction in morbidity and mortality associated with AIDS. This happens because the incidence of the major opportunistic infections and of many AIDS-related neurological disorders dramatically decreased, but the Progressive Multifocal Leukoencephalopathy (PML) is still observed with a prevalence up to 5% in AIDS patients. Although the advent of HAART did not affect so much the incidence of PML, some changes in the clinical course of this fatal disease have been observed. In fact PML usually results in death within 3-6 months of diagnosis (PML fast progressing patients), but to date there are reports of remission of PML during HAART and several PML cases have prolonged rate of survival, up to one year from the onset of the disease (PML slow progressing patients). In this project we are hypothesizing that either a particular JCV genotype or a specific TCR rearrangement or both could affect the disease progress, slowing down the process of demyelination. Moreover several cases suffering with a PML-like Leukoencephalopathy, called non- determined Leukoencephalopathy (NDLE) with no evidence of JCV genome in CSF have been lately reported. Our suggestion is that the result of an improved immune status upon HAART could also lead to an imbalanced expression of cytokines and immunomodulators by peripheral lymphocytes that may affect. In order to verify our hypothesis and better understand the etiology, the development and the progress of the new variant of PML and of the novel JCV negative-leukoencephalopathy, we are proposing to enroll in a longitudinal study, patients affected with fast and slow progressing PML, patients with suspected NDLE, HIV+ patients without any neurological disorders and healthy controls, whose biological samples will be collected at different times of the diseases and subjected to immunological, virological, genetic conventional and innovative examinations as described in the proposal.

描述（由申请人提供）：在治疗 HIV 感染时使用更强化的抗逆转录病毒疗法（例如 HAART）已导致与 AIDS 相关的发病率和死亡率显着降低。发生这种情况是因为主要机会性感染和许多与 AIDS 相关的神经系统疾病的发病率急剧下降，但仍观察到进行性多灶性白质脑病 (PML) 在 AIDS 患者中的患病率高达 5%。尽管HAART的出现并没有对PML的发病率产生太大影响，但是已经观察到这种致命疾病的临床病程发生了一些变化。事实上，PML 通常会在诊断后 3-6 个月内导致死亡（PML 快速进展的患者），但迄今为止，有报道称在 HAART 期间 PML 得到缓解，并且一些 PML 病例的生存率延长，从发病起长达一年疾病（PML 进展缓慢的患者）。在这个项目中，我们假设特定的 JCV 基因型或特定的 TCR 重排或两者都可能影响疾病进展，减缓脱髓鞘过程。此外，最近还报道了几例患有 PML 样白质脑病的病例，称为未确定白质脑病 (NDLE)，且脑脊液中没有 JCV 基因组证据。我们的建议是，HAART 后免疫状态改善的结果也可能导致外周淋巴细胞细胞因子和免疫调节剂的表达失衡，从而可能产生影响。为了验证我们的假设并更好地了解 PML 新变种和新型 JCV 阴性白质脑病的病因、发生和进展，我们建议对患有快速和缓慢进展 PML 的患者进行一项纵向研究。疑似NDLE患者、无任何神经系统疾病的HIV阳性患者和健康对照者，将在疾病发生的不同时间采集其生物样本，并按照提案中所述进行免疫学、病毒学、遗传学常规和创新检查。