SIV Encephalitis and Disease Progression

SIV 脑炎和疾病进展

• 批准号: 7410082
• 负责人: Clayton A. Wiley
• 金额: $ 61.64万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7410082
• 关键词: AIDS Dementia Complex; Acquired Immunodeficiency Syndrome; Address; Animal Disease Models; Animals; Autopsy; Benzodiazepine Receptor; Binding; Blood; Brain; Brain region; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Count; Complex; DAA 1106; Development; Disease; Disease Progression; Encephalitis; Exhibits; Extracellular Matrix; HIV Infections; HIV encephalitis; Human; Immune; Individual; Infection; Infiltration; Left; Ligand Binding; Ligands; Macaca; Macaca mulatta; Macaca nemestrina; Measurement; Measures; Microglia; Modeling; Monitor; Nervous system structure; Neurodegenerative Disorders; Neuropathogenesis; Opportunistic Infections; Pathogenesis; Patients; Peripheral; Peripheral Blood Mononuclear Cell; Population; Positron-Emission Tomography; Research Personnel; SIV; SIV encephalitis; Scanning; Serum; Stream; Synapses; Systemic disease; Systemic infection; T-Lymphocyte; Testing; Tissues; Variant; Viral; Viral Load result; Viremia; Virus; Week; brain tissue; experience; extracellular; immunosuppressed; macrophage; monocyte; neuropathology; radioligand; research study; theories; therapeutic target; trafficking

DESCRIPTION (provided by applicant): Approximately 1/4 of immunosuppressed AIDS patients develop a neurodegenerative disorder clinically characterized as HIV associated dementia complex. In our experience, autopsies of AIDS patients who had become demented for reasons other than opportunistic infection uniformly demonstrated HIV encephalitis. Why there is such an abundance of activated and infected macrophages in the CNS remains an enigma, however, we theorize that it may be due to increased trafficking of HIV-infected monocytes. Monocytes are activated upon leaving the blood stream and entering the CNS where they transform into macrophages and can initiate viral replication and a neuroinflammatory cascade. Tissue damage begins a cycle of astrocytic and microglial activation, providing susceptible targets for further HIV infection and destruction of synaptic connectivity. We propose to use SIV infection of Macaca nemestrina and Macaco mullata as models of HIV encephalitis to test several hypotheses related to our theory of lentiviral neuropathogenesis. While no animal disease model is perfect, numerous similarities between simian and human nervous systems, between SIV and HIV infection and the capacity to manipulate and monitor CNS damage, make the macaque models optimal for these studies. Our overarching hypothesis is: Progression of SIV infection leads to increased monocyte/macrophage infection and trafficking into the CNS with destruction of the synaptic matrix. For all 3 aims of the current proposal, we will study a group of 36 SIV infected macaques. At 2-week intervals we will measure; absolute CD4 and CD8 T-cell counts and viral loads in the CSF and serum of all animals. In Specific Aim 1 we will examine the relationship between peripheral SIV infection and the development of SIV encephalitis. These experiments will test the hypothesis that: with progression of immune suppression there is increased trafficking of SIV infected monocytes causing increased brain viral burden. In Specific Aim 2 we will assess activation of CNS macrophages using Positron Emission Tomography and the peripheral benzodiazepine receptor radioligand [11C]-DAA1106. We hypothesize that when animals begin to show disease progression (decline in CD4 T-cells, increase in viremia) they will show increased CSF virus and increased binding of DAA1106 consistent with activation of CNS macrophages. In Specific Aim 3 we will measure synaptic and extracellular matrix damage in autopsy brain tissues and compare them to the temporal course of peripheral and central viral loads, DAA1106 binding. In summary, the proposed specific aims will test a set of interconnected hypotheses helping define mechanisms of synaptic damage and therapeutic targets to arrest its development and progression.

描述（由申请人提供）：大约1/4的免疫抑制艾滋病患者发展为神经退行性疾病，临床特征为HIV相关痴呆复合体。根据我们的经验，由于机会性感染以外的原因导致精神错乱的艾滋病患者的尸检一致证明是艾滋病毒脑炎。为什么在中枢神经系统中有如此丰富的活化和感染巨噬细胞仍然是一个谜，然而，我们推测这可能是由于hiv感染单核细胞的贩运增加。单核细胞在离开血流进入中枢神经系统时被激活，在那里它们转化为巨噬细胞，可以启动病毒复制和神经炎症级联反应。组织损伤开始星形细胞和小胶质细胞激活周期，为进一步的HIV感染和突触连通性破坏提供易感靶点。