Role of CNS Opportunistic Infections in Subsequent Development of HIV Encephaliti

描述(由申请人提供)：感染C分支病毒的国家很少报告艾滋病毒痴呆症。然而，神经系统的机会性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%的患者有中枢神经系统症状，其中大部分是机会性感染。由于这些感染是可以治疗的，因此确定这些感染对大脑的长期影响是当务之急。初步数据显示，与这些感染相关的炎症浸润物中有大量感染艾滋病毒的巨噬细胞。然而，目前尚不清楚与机会性感染相关的炎性渗透是否可以作为艾滋病毒进入的门户，以及病毒是否随后可能在大脑中驻留，然后继续在大脑中进化。这些菌株可能导致神经胶质细胞功能障碍的程度尚不清楚。此外，目前尚不清楚脑膜浸润性病变的风险是否与实质浸润性病变的风险相似。研究艾滋病毒C分支病毒感染的这些神经病理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来解决关于疾病发病机制的问题，否则就不可能完成。因此，我们建议：1.确定患有中枢神经系统弓形虫病或肺结核的HIV感染患者的神经胶质细胞激活和神经元损伤的程度。2.鉴定和比较中枢神经系统弓形虫病或结核病相关炎性浸润物中HIV感染细胞的病毒序列。3.确定炎性浸润物中脑源性序列env和Tat是否在体外引起神经胶质细胞激活或神经元损伤。这些目标将通过约翰霍普金斯大学和NIMHANS之间的合作努力实现。在过去的几年里，这两个机构之间已经建立了良好的工作关系。我们还为NIMHANS调查人员制定了一项培训和技术转让计划。 公共卫生相关性：中枢神经系统机会性感染是发展中国家艾滋病毒感染人群发病率和死亡率的主要原因，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尚不清楚。利用来自印度的独特的人脑尸检组织资源，结合组织病理学、分子和细胞方法，我们将确定在机会性感染的背景下病毒进入大脑的机制，并将确定这些感染对未感染的脑细胞的影响。这些信息将对制定长期管理艾滋病毒感染机会性感染患者的指导方针至关重要。

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.