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: 7489255
• 负责人: AVINDRA NATH
• 金额: $ 34.4万
• 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/7489255
• 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; Developed Countries; Developing Countries; Development; Disease; Economics; 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; Nervous system structure; Neuroglia; Neurologic; Neurologic Manifestations; Neuronal Injury; Neurosciences; Numbers; Opportunistic Infections; Outpatients; Pathogenesis; Patients; Pharmaceutical Preparations; Population; Principal Investigator; Public Health; Range; 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; mild neurocognitive impairment; mortality; prevent; programs; psychologic; residence

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）：艾滋病毒痴呆症很少报道来自感染进化枝C病毒的国家。然而，神经系统的机会主义感染是这些发展中国家发病和死亡率的主要原因。例如，在印度，有近500万患者感染了该病毒，据估计，近25％的患者患有中枢神经系统表现，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。初步数据表明，与这些感染相关的炎症性浸润有大量感染的HIV感染巨噬细胞。但是，如果与机会性感染相关的炎症性浸润物可能是HIV的入口门户，并且该病毒可能会在大脑中建立住所，然后继续在大脑内发展，则尚不清楚。这些菌株可能引起神经膜细胞功能障碍的程度仍然未知。此外，脑膜浸润的患者是否与实质浸润的患者面临类似的风险，尚不清楚。研究HIV进化枝C病毒感染的这些神经病理学后果的主要局限性是这些国家缺乏尸检组织。 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，这是来自亚洲和非洲艾滋病毒感染患者的唯一表征良好的脑组织标本的来源。这是解决有关疾病发病机理问题的绝佳机会，否则就无法做到。因此，我们建议1。确定感染性中枢神经系统吞噬或结核病患者的HIV感染患者的神经胶质细胞激活和神经元损伤的程度。 2。鉴定和比较与CNS弓形虫病或结核病有关的炎症性浸润中HIV感染细胞的病毒序列。 3。确定炎症性浸润中Env和Tat的脑衍生序列是否会导致神经胶质细胞激活或体外神经元损伤。这些目标将通过约翰·霍普金斯大学和尼姆汉斯之间的合作努力来实现。在过去的几年中，这两个机构之间已经建立了一个很好的工作关系。我们还为Nimhans调查人员制定了一项培训和技术转移计划。 公共卫生相关性：中枢神经系统的机会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，但是，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。利用印度的人脑尸检组织的独特资源以及组合的组织病理学，分子和细胞方法，在机会性感染的环境下，病毒进入大脑的机制，还将确定这些感染对未感染脑细胞的影响。该信息对于制定了有机会感染的HIV感染患者的长期管理指南至关重要。