CNS Immune/Inflammatory Biomarkers in HIV Controllers

描述(由申请人提供)：控制者被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2000拷贝或以下的个人。我们之前的工作显示，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CD8+T细胞反应。尽管他们有能力遏制病毒复制，但这些人形成了一个不同的群体；至少其中一些人最终发展到CD4下降和艾滋病定义的疾病。在初步研究中，艾滋病毒控制者的脑脊液病毒载量显著高于接受HAART且病毒血症被抑制的艾滋病毒阳性患者(P&lt；0.0001)。与HIV阴性个体相比，控制组的脑脊液新喋呤和IP-10水平也升高。因此，一些HIV控制者有脑脊液病毒血症和中枢神经系统免疫激活标志的升高。这些患者提供了一个独特的机会来研究有助于免疫控制的机制，以及中枢神经系统中获得性免疫和免疫激活/炎症之间的平衡。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、影像和神经心理学的临床研究人员来确定HIV控制者中枢神经系统炎症和/或损伤的程度，并确定这些人中受控或活跃的CNS感染的相关性。我们将集中于(A)HIV特异性免疫反应；(B)T细胞激活的标志物；(C)神经元损伤的可溶性脑脊液生物标志物；(D)4特斯拉MRS测量的脑代谢标志物；以及(E)神经心理测试。在具体目标1中，我们将研究HIV控制者和匹配对照组(即VL&GT；10,000 vRNA拷贝/毫升的非控制者；VL&LT；50拷贝/毫升的HAART抑制者；HIV阴性对照组)血浆和脑脊液病毒血症与HIV特异性T细胞反应之间的关系。在特定的目标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/免疫激活、神经损伤和临床状态的生物标记物之间的关系。这项建议中的研究将确定CNS参与HIV控制者的程度，并调查在没有HAART的情况下控制局部CNS感染的免疫学机制。在这一独特的受试者组中确定中枢神经系统免疫控制的相关因素可能有助于开发治疗方法，以减轻或阻止所有艾滋病毒感染者中枢神经系统中艾滋病毒的有害影响。 公共卫生相关性：艾滋病毒控制员代表了一组独特的个人，他们在缺乏高效抗逆转录病毒治疗(HAART)的情况下控制血浆艾滋病毒RNA水平。然而，一些艾滋病毒控制者会经历CD4T细胞下降和疾病进展。该项目的目标是确定HIV控制者中枢神经系统(CNS)参与的程度，并研究在没有HAART的情况下控制局部CNS感染的免疫学机制。

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.