CNS Immune/Inflammatory Biomarkers in HIV Controllers

HIV 控制者的中枢神经系统免疫/炎症生物标志物

• 批准号: 7939616
• 负责人: Barbara L. Shacklett
• 金额: $ 22.55万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-25 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7939616
• 关键词: Affect; Antigens; Automobile Driving; Biological Markers; Blood; Blood Cells; CCL2 gene; CD4 Lymphocyte Count; CD4 Positive T Lymphocytes; CD8B1 gene; CXCL10 gene; Central Nervous System Infections; Cerebrospinal Fluid; Cerebrospinal Fluid Proteins; Cerebrum; Choline; Clinical; Clinical Data; Clinical Immunology; Clinical Investigator; Detection; Disease Progression; Equilibrium; Exhibits; Glutamates; Goals; HIV; HIV Infections; HLA-DR Antigens; Highly Active Antiretroviral Therapy; Image; Immune; Immune response; Immunotherapy; Individual; Inflammation; Inflammatory; Injury; Lead; Light; MHC Class I Genes; Maps; Measures; Methods; Mucosal Immune Responses; Mucous Membrane; N-acetylaspartate; Neopterin; Nervous System Trauma; Neuraxis; Neurology; Neuronal Injury; Neuropsychological Tests; Neuropsychology; Patients; Performance; Peripheral; Plasma; Price; Process; RNA; Recruitment Activity; Relative (related person); Research Personnel; San Francisco; Site; Study Subject; Systemic disease; T cell response; T-Cell Activation; T-Lymphocyte; Tissues; Viral; Viral Load result; Viremia; Work; adaptive immunity; clinically significant; cohort; comparison group; design; experience; gastrointestinal; immune activation; myoinositol; neurofilament; novel strategies; public health relevance; tau Proteins; therapy development; vaccine development

DESCRIPTION (provided by applicant): Controllers are defined as individuals who control plasma HIV RNA levels to 2,000 copies or below for many years in the absence of highly active antiretroviral therapy (HAART). Our previous work revealed that many Controllers have unusually strong, polyfunctional HIV-specific CD8+ T-cell responses at tissue sites of viral replication, such as the gastrointestinal mucosa. Despite their ability to contain viral replication, these individuals form a heterogeneous group; at least some of whom ultimately progress to CD4 decline and AIDS-defining illnesses. In preliminary studies, HIV Controllers had significantly higher CSF viral loads than HIV+ patients on HAART with suppressed viremia (P<0.0001). Controllers also had elevated CSF neopterin and IP-10 relative to HIV negative individuals. Thus, some HIV Controllers have CSF viremia and elevated markers of CNS immune activation. These patients represent a unique opportunity to study the mechanisms contributing to immune control, and the balance between adaptive immunity and immune activation/inflammation in the CNS. This collaborative R21 proposal will draw on an unusually well characterized group of HIV Controllers and a group of clinical investigators in Immunology, Clinical Neurology, Imaging, and Neuropsychology to determine the extent of CNS inflammation and/or injury in HIV Controllers, and to identify correlates of controlled or active CNS infection in these individuals. We will focus on (a) HIV-specific immune responses; (b) markers of T-cell activation; (c) soluble CSF biomarkers of neuronal injury; (d) cerebral metabolite markers measured by 4 Tesla MRS; and (e) neuropsychological testing. In Specific Aim 1, we will examine the relationship between plasma and CSF viremia and HIV-specific T-cell responses in HIV Controllers and matched comparison groups (i.e., Non-Controllers with VL >10,000 vRNA copies/mL; HAART-suppressed individuals with VL <50 copies/mL; HIV negative controls). In Specific Aim 2, we will examine the relationship between the parameters assessed in Aim 1 and biomarkers of inflammation/immune activation, neurological damage, and clinical status in the same subject groups. The studies in this proposal will determine the extent of CNS involvement in HIV Controllers, and investigate the immunological mechanisms underlying control of local CNS infection in the absence of HAART. Identification of correlates of immune control in the CNS in this unique group of subjects may facilitate the development of therapies that can mitigate or arrest the injurious effects of HIV in the CNS in all HIV-infected subjects. PUBLIC HEALTH RELEVANCE: HIV Controllers represent a unique group of individuals who control plasma HIV RNA levels in the absence of highly active antiretroviral therapy (HAART). Nevertheless, some HIV Controllers experience CD4 T-cell decline and disease progression. The goal of this project is to determine the extent of central nervous system (CNS) involvement in HIV controllers, and investigate the immunological mechanisms underlying control of local CNS infection in the absence of HAART.

描述（由申请人提供）：控制者定义为在缺乏高效抗逆转录病毒治疗（HAART）的情况下，多年来将血浆HIV RNA水平控制在2，000拷贝或以下的个体。我们以前的工作表明，许多控制者在病毒复制的组织部位（如胃肠道粘膜）具有异常强烈的多功能HIV特异性CD 8 + T细胞应答。尽管他们有能力遏制病毒复制，但这些人形成了一个异质性群体;其中至少有一些人最终发展为CD 4下降和艾滋病定义疾病。在初步研究中，HIV控制者的CSF病毒载量显著高于HAART治疗的HIV+患者（P<0.0001）。相对于HIV阴性个体，控制者的CSF新蝶呤和IP-10也升高。因此，一些HIV控制者具有CSF病毒血症和升高的CNS免疫活化标志物。这些患者代表了研究有助于免疫控制的机制以及CNS中适应性免疫和免疫活化/炎症之间的平衡的独特机会。这项合作的R21提案将利用一组特征异常良好的HIV控制者和一组免疫学、临床神经学、成像学和神经心理学的临床研究人员来确定HIV控制者的中枢神经系统炎症和/或损伤的程度，并确定这些个体中受控或活动性中枢神经系统感染的相关性。我们将重点关注（a）HIV特异性免疫反应;（B）T细胞活化标志物;（c）神经元损伤的可溶性CSF生物标志物;（d）通过4特斯拉MRS测量的脑代谢物标志物;和（e）神经心理学测试。在具体目标1中，我们将研究血浆和CSF病毒血症与HIV控制者和匹配对照组（即，VL > 10，000 vRNA拷贝/mL的非控制者; VL <50拷贝/mL的HAART抑制个体; HIV阴性对照）。在特定目标2中，我们将检查目标1中评估的参数与相同受试者组中炎症/免疫活化、神经损伤和临床状态的生物标志物之间的关系。本提案中的研究将确定HIV控制者中枢神经系统受累的程度，并研究在没有HAART的情况下控制局部中枢神经系统感染的免疫学机制。在这组独特的受试者中鉴定CNS中免疫控制的相关性可能有助于开发可以减轻或阻止HIV在所有HIV感染受试者中CNS中的损伤作用的疗法。 公共卫生关系：HIV控制者代表了一组独特的个体，他们在没有高效抗逆转录病毒治疗（HAART）的情况下控制血浆HIV RNA水平。然而，一些HIV控制者经历了CD 4 T细胞下降和疾病进展。本项目的目标是确定中枢神经系统（CNS）参与HIV控制者的程度，并研究在没有HAART的情况下控制局部CNS感染的免疫学机制。