Pathogenesis of leukoencephalopathies in HIV+ patients

HIV患者白质脑病的发病机制

• 批准号: 7072721
• 负责人: PASQUALE FERRANTE
• 金额: $ 23.73万
• 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/7072721
• 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）：使用更密集的抗逆转录病毒疗法（例如HAART）在艾滋病毒感染治疗中的使用导致与艾滋病相关的发病率和死亡率显着降低。之所以发生这种情况，是因为主要的机会性感染和许多与AIDS相关的神经系统疾病的发生率显着降低，但是在AIDS患者中，进行性多灶性白细胞厌氧（PML）仍被观察到高达5％的患病率。尽管HAART的出现并没有太大影响PML的发病率，但已经观察到这种致命疾病的临床病程的某些变化。实际上，PML通常会在诊断后的3-6个月内导致死亡（PML快速进展患者），但迄今为止，有报道称HAART期间PML缓解，几例PML病例的生存率延长，从疾病发作后长达一年（PML缓慢进展的患者）。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，从而减慢脱髓鞘的过程。此外，最近有几例患有PML样的白细胞脑病，称为非确定的白细胞脑病（NDLE），而CSF中没有JCV基因组的证据。我们的建议是，HAART上的免疫状态改善的结果也可能导致可能影响的周围淋巴细胞对细胞因子和免疫调节剂的表达不平衡。 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如该提案所述，接受免疫，病毒学，遗传常规和创新性检查。