Critical Role of Cytotoxic T Cells in HIV Neuropathogenesis

细胞毒性 T 细胞在 HIV 神经发病机制中的关键作用

• 批准号: 9341385
• 负责人: SERENA S SPUDICH
• 金额: $ 56.11万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9341385
• 关键词: Acute; Affect; Aftercare; Alzheimer' s Disease; Anti-Retroviral Agents; Apoptosis; Apoptotic; Appearance; Biological Assay; Brain; CD8B1 gene; Cell Count; Cells; Central Nervous System Diseases; Cerebrospinal Fluid; Chronic; Clinical Markers; Clone Cells; Cohort Studies; Complex; Cytotoxic T-Lymphocytes; Data; Disease remission; Encephalitis; Enrollment; Exposure to; Feasibility Studies; Frequencies; Gene Expression; HIV; HIV Antigens; HIV Infections; HIV-associated neurocognitive disorder; High Prevalence; Impaired cognition; Individual; Infection; Infiltration; Inflammation; Inflammatory; Injury; Intervention; Lead; Lymphocyte; Magnetic Resonance Spectroscopy; Measures; Mediating; Military Personnel; Multiple Sclerosis; Neuraxis; Neurodegenerative Disorders; Neuronal Injury; Neurons; Neuropathogenesis; Neuropsychological Tests; Pathogenesis; Pathogenicity; Patients; Phenotype; Population; Predisposition; RNA; Recruitment Activity; Research; Residual state; Role; Sampling; Specificity; T-Lymphocyte; Thailand; Tissues; Viral; Viral reservoir; Virus Replication; antiretroviral therapy; base; brain tissue; central nervous system injury; cognitive function; cohort; cytokine; cytotoxicity; experimental study; immunological status; injured; innovation; mitochondrial dysfunction; nervous system disorder; neuroinflammation; novel; performance tests; prevent; programs; therapeutic development; trafficking

PROJECT SUMMARY HIV infects the central nervous system (CNS) within days of initial exposure and has the propensity to cause progressive neuropathogenesis despite the intervention of antiretroviral therapy (ART). Infiltration by cytotoxic T cells (CTLs) into the CNS is a recognized feature in many neurodegenerative diseases that are associated with neuroinflammation, including multiple sclerosis, Alzheimer's disease, and various encephalitides but their role in HIV neuropathogenesis remains unknown. In HIV infection, CTLs constitute the majority of lymphocytes in the CSF, occur at a higher frequency than in many other neurological diseases, and are not normalized by ART. Our preliminary analyses show that this is already occurring within the first weeks after HIV exposure. Despite the large presence of CTLs in the CNS from the early stage of HIV infection, their role in neuropathogenesis remains mostly unknown. We hypothesize that hyperactivated CTLs in the CNS of untreated acute infected donors are a major cause of CNS damage. We further hypothesize that ART initiation during acute infection preserves beneficial HIV-specific CTLs in the brain, controlling viral reservoirs. Finally, we hypothesize that among individuals who initiate treatment during chronic infection T cell unique clones persist in the CNS after treatment initiation and are associated with residual CNS damage in this setting. The major objective of this proposal is to determine the neuropathogenic mechanisms of CTLs during HIV infection in acute and chronic infection prior to and after ART initiation. To achieve this objective, we will analyze CTLs in the CSF from a highly unique cohort enrolling in Bangkok, Thailand (U.S. Military HIV Research Program study RV254), that is recruiting subjects in the earliest stages of acute infection and compare them to chronically infected subjects. At enrollment, all subjects initiate ART, PBMCs and CSF samples are collected and markers of neuroinflammation in the CSF, magnetic resonance spectroscopy and neuropsychological testing performance are measured at baseline, weeks 24 and 96. We will be able to determine how early are CTLs entering the CNS and causing damage, define the cellular mechanisms involved in the CTL-mediated neuropathogenesis prior to treatment and whether early antiretroviral treatment decreases HIV reservoir in CNS and prevents residual damage persisting under ART. Understanding the neuropathogenic mechanisms that are established in the first days following exposure and whether they persist with ART is of critical importance to reduce the burden of CNS injury among the HIV-infected population. The results of this study will pave the way for the development of therapeutic strategies to limit CTL-mediated CNS damage and preserve cognitive function in HIV-infected patients.

项目摘要 HIV在初次接触后数天内感染中枢神经系统（CNS），并有可能导致 尽管抗逆转录病毒治疗（ART）的干预，进行性神经发病机制。细胞毒性浸润 T细胞（CTL）进入CNS是许多神经退行性疾病的公认特征， 神经炎症，包括多发性硬化症，阿尔茨海默病，和各种脑炎，但他们的 在HIV神经发病机制中的作用仍不清楚。在HIV感染中，CTL构成淋巴细胞的大部分 在CSF中，发生频率比许多其他神经系统疾病更高，并且不能通过 条我们的初步分析表明，这种情况已经发生在艾滋病毒暴露后的第一周内。 尽管从HIV感染的早期阶段开始，在CNS中大量存在CTL，但它们在HIV感染中的作用仍然存在。 神经发病机制仍然是未知的。我们假设，在中枢神经系统中过度活化的CTL， 未经治疗的急性感染供体是CNS损伤的主要原因。我们进一步假设， 在急性感染期间，在大脑中保留有益的HIV特异性CTL，控制病毒储存库。最后， 我们假设在慢性感染期间开始治疗的个体中，T细胞独特克隆 在治疗开始后持续存在于CNS中，并与这种情况下的残留CNS损伤相关。的 这项计划的主要目的是确定HIV感染过程中CTL的神经致病机制 在急性和慢性感染之前和之后开始抗逆转录病毒治疗。为了实现这一目标，我们将分析CTL 在泰国曼谷招募的一个非常独特的队列中， 研究RV254），即招募急性感染最早期的受试者，并将其与 慢性感染者入组时，所有受试者开始ART，采集PBMC和CSF样本 和CSF中的神经炎症标志物，磁共振波谱和神经心理学 在基线、第24周和第96周测量测试性能。我们将能够确定 CTL进入CNS并引起损伤，定义了CTL介导的CNS损伤中涉及的细胞机制。 治疗前的神经发病机制，以及早期抗逆转录病毒治疗是否减少了艾滋病毒储存库， 中枢神经系统和预防残留损伤持续下艺术。了解神经致病机制 在暴露后的第一天建立，以及他们是否坚持ART至关重要 减少HIV感染人群中CNS损伤负担的重要性。这项研究的结果将 为开发治疗策略以限制CTL介导的CNS损伤和保护 HIV感染者的认知功能。