Role of CNS Opportunistic Infections in Subsequent Development of HIV Encephaliti

中枢神经系统机会性感染在艾滋病毒脑炎后续发展中的作用

• 批准号: 7885443
• 负责人: CARLOS A PARDO-VILLAMIZAR
• 金额: $ 32.47万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7885443
• 关键词: Acquired Immunodeficiency Syndrome; Address; Africa; African; Anti-Retroviral Agents; Area; Asia; Asians; Autopsy; Brain; Cells; Central Nervous System Diseases; Cercopithecine Herpesvirus 1; Chemokine (C-C Motif) Receptor 5; Collaborations; Country; Data; Dementia; Developing Countries; Development; Disease; Functional disorder; Goals; Guidelines; HIV; HIV encephalitis; HIV-1; Human; Human Resources; In Vitro; Incidence; India; Infection; Inflammatory Infiltrate; Institution; Knowledge; Lead; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Meningeal; Microglia; Molecular; Morbidity - disease rate; National Institute of Mental Health; National Institute of Neurological Disorders and Stroke; Nervous system structure; Neuroglia; Neurologic; Neurologic Manifestations; Neuronal Injury; Neurosciences; Opportunistic Infections; Outpatients; Pathogenesis; Patients; Pharmaceutical Preparations; Population; Principal Investigator; Reporting; Research Personnel; Risk; Role; Source; Specimen; Staging; Survivors; Techniques; Technology Transfer; Tissues; Toxoplasmosis; Training; Tuberculosis; Universities; Viral; Virus; Virus Diseases; Work; brain cell; brain tissue; chemokine receptor; macrophage; meetings; mild neurocognitive impairment; mortality; prevent; programs; psychologic; public health relevance; residence; socioeconomics

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.

描述（由申请人提供）：感染 C 分支病毒的国家很少报告 HIV 痴呆。然而，神经系统的机会性感染是这些发展中国家发病和死亡的主要原因。例如，在印度有近500万患者感染病毒，估计近25%的患者有中枢神经系统表现，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症浸润有大量 HIV 感染的巨噬细胞。然而，目前尚不清楚与机会性感染相关的炎症浸润是否可以作为艾滋病毒的进入门户，以及病毒是否可以在大脑中定居并继续在大脑内进化。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是否会面临与实质浸润患者相似的风险。研究 HIV C 分支病毒感染的这些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 是一家独特的机构，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的明确特征脑组织标本的唯一来源。这是解决有关疾病发病机制问题的绝佳机会，而其他方法则无法解决这些问题。因此，我们建议： 1. 确定患有中枢神经系统弓形虫病或结核病的 HIV 感染患者的神经胶质细胞活化和神经元损伤的程度。 2. 鉴定和比较与 CNS 弓形体病或结核病相关的炎症浸润中 HIV 感染细胞的病毒序列。 3. 确定炎症浸润中脑源性 env 和 tat 序列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 之间的合作努力来实现。过去几年里，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：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。利用来自印度的独特的人类大脑尸检组织资源，并结合组织病理学、分子和细胞方法，我们将确定机会性感染情况下病毒进入大脑的机制，并将确定这些感染对未感染大脑的影响细胞。这些信息对于制定艾滋病毒感染者机会性感染的长期管理指南至关重要。