Role of CNS Opportunistic Infections in Subsequent Development of HIV Encephaliti

描述（由申请人提供）：感染C型病毒的国家很少报告艾滋病毒痴呆症。然而，神经系统的寄生虫感染是这些发展中国家发病率和死亡率的主要原因。例如，在印度，有近500万患者感染该病毒，据估计，近25%的患者有CNS表现，其中大多数是机会性感染。由于这些感染是可以治疗的，因此必须确定这些感染对大脑的长期影响。初步数据显示，与这些感染相关的炎性浸润有大量的HIV感染的巨噬细胞。然而，与机会性感染相关的炎性浸润是否可以作为HIV进入的门户，以及病毒是否可以在大脑中建立驻留并继续在大脑中进化，这仍然是未知的。这些菌株可能导致神经胶质细胞功能障碍的程度仍然未知。此外，尚不清楚脑膜浸润患者的风险是否与实质浸润患者相似。研究HIV C分支病毒感染的神经病理学后果的一个主要限制是缺乏来自这些国家的尸检组织。NIMHANS是一个独特的机构，自1990年以来一直对死于艾滋病的患者进行尸检。据我们所知，这是亚洲和非洲艾滋病毒感染者脑组织标本的唯一来源。这是一个很好的机会，以解决有关疾病的发病机制，否则不可能做到的问题。因此，我们建议，1。目的：探讨HIV感染合并中枢神经系统弓形虫病或结核病患者神经胶质细胞活化和神经元损伤的程度。2.鉴定和比较CNS弓形体病或结核相关炎性浸润中HIV感染细胞的病毒序列。3.确定炎性浸润中env和达特的脑源性序列是否在体外引起胶质细胞活化或神经元损伤。这些目标将通过约翰霍普金斯大学和NIMHANS之间的合作努力来实现。过去几年来，这两个机构之间已经建立了良好的工作关系。我们还为NIMHANS调查人员制定了培训和技术转让计划。 公共卫生相关性：CNS机会性感染是发展中国家HIV感染人群发病和死亡的主要原因，然而，这些疾病对成功治疗这些感染的患者大脑的长期影响仍然未知。使用来自印度的人脑尸检组织的独特资源和组织病理学，分子和细胞方法相结合，我们将确定病毒进入大脑的机制，在机会性感染的背景下，还将确定这些感染对未感染脑细胞的影响。这一信息将是至关重要的，在制定长期管理的艾滋病毒感染患者的机会性感染的指导方针。

DESCRIPTION (provided by applicant): HIV dementia has only rarely been reported from countries infected with clade C virus. Opportunistic infections of the nervous system, however, are a major cause of morbidity and mortality in these developing countries. For example, in India where there are nearly 5 million patients are infected with the virus, it was estimated that nearly 25% of patients have CNS manifestations, most of which are opportunistic infections. Since these infections are treatable, it is imperative to determine the long-term impact of these infections on the brain. Preliminary data shows that the inflammatory infiltrates associated with these infections have a large number of HIV infected macrophages. It remains unknown, however, if inflammatory infiltrates associated with the opportunistic infection may serve as a portal of entry for HIV and if the virus may then establish residence in the brain and then continue to evolve within the brain. The degree to which these strains may cause neuro-glial cell dysfunction remains unknown. Further it remains unknown if patients with meningeal infiltrates would be at similar risks as those with parenchymal infiltrates. A major limitation to studying these neuropathological consequences of HIV clade C virus infection is the lack of autopsy tissues from these countries. NIMHANS is a unique institution that has conducted autopsies on patients that have died of AIDS since 1990. To the best of our knowledge, this is the only source of well characterized brain tissue specimens from HIV infected patients in Asia and Africa. This represents an excellent opportunity to address questions about disease pathogenesis that could not have been done otherwise. We thus propose to, 1. To determine the extent of glial cell activation and neuronal injury in HIV infected patients with CNS toxoplasmosis or tuberculosis. 2. To identify and compare viral sequences from HIV infected cells in inflammatory infiltrates associated with CNS toxoplasmosis or tuberculosis. 3. To determine if brain derived sequences of env and tat in inflammatory infiltrates cause glial cell activation or neuronal injury in vitro. These goals will be accomplished through collaborative efforts between Johns Hopkins University and NIMHANS. An excellent working relationship has already been established between the two institutions over the last several years. We have also devised a plan for training and technology transfer for the NIMHANS investigators. PUBLIC HEALTH RELEVANCE: CNS opportunistic infections are the major cause of morbidity and mortality in HIV infected populations in the developing world, however, the long-term impact of these diseases on the brain of patients successfully treated for these infections remains unknown. Using a unique resource of human brain autopsy tissue from India and a combined histopathological, molecular and cellular approach we will determine the mechanism of viral entry into the brain in the setting of the opportunistic infection and will also determine the impact of these infections on uninfected brain cells. This information will be critical in developing guidelines for long-term management of HIV-infected patients with opportunistic infections.