Immune Correlates of Protection in Drug-Resistant HIV

耐药艾滋病毒保护的免疫相关性

• 批准号: 6841563
• 负责人: BRINDA EMU
• 金额: $ 12.18万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6841563
• 关键词: AIDS therapy; HIV infections; age difference; antiAIDS agent; clinical research; combination chemotherapy; cytotoxic T lymphocyte; disease /disorder etiology; drug resistance; helper T lymphocyte; human immunodeficiency virus; human subject; immune response; immunization; longitudinal human study; patient oriented research; phenotype; prognosis; virus load; virus replication

DESCRIPTION (provided by applicant): My goals in seeking a K23 award are to investigate HIV infection and to develop a career in translational research. My particular research interest is in the determination of important immune responses needed in an effective preventative or therapeutic HIV vaccine. I have assembled a mentoring committee composed of internationally recognized scientists with strong track records in translational research; I will obtain training in clinical research methodologies and additional laboratory training in immunologic methodologies; and I propose to conduct a series of mentored research projects that will provide opportunities for me to acquire the "hands-on" training needed to become a productive, independent clinical researcher. Many HIV-infected patients have low levels of HIV viral replication despite antiretroviral therapy. This viremia represents drug-resistant virus with reduced replicative capacity. These patients maintain increased CD4+ T cell counts. A significant proportion of these patients, however, will ultimately develop high-level viremia. I am interested in investigating the immunologic parameters that may predict which patients may develop high-level viremia, as well as study the effect of drug-resistant viremia on the entire immune system. I propose the following specific aims: (1) To assess whether higher HIV-specific CD4+ and CD8+ T cell responses are associated with the control of drug-resistant HIV replication in patients on antiretroviral therapy; (2) To assess whether evidence of an aging immune system is associated with CD4+ T cell loss in patients with partially controlled viremia on antiretroviral therapy; (3) To assess whether the ability of T cells to respond to immunization is altered in patients with partially controlled viremia on antiretroviral therapy. We hypothesize that the maintenance of high-level HIV-specific T cell responses will predict maintenance of partial control of viremia; we will follow these patients longitudinally with serial measurements of HIV-specific T cell function. Furthermore, the presence of partial HIV viremia is associated with an increased proportion of effector CD4+ T cells, a sign of an aging immune system. We hypothesize that these patients will sustain CD4+ T cell loss; we will follow them with serial measurements of T cell immunophenotyping. In addition, we hypothesize that patients with partial viremic control will have reduced responses to immunization, an estimate of in vivo immune competence. For Aims 1 and 2, I will use samples collected in an established cohort study. For Aim 3, I will conduct a prospective interventional study, where I will design and implement an independent clinical research project.

描述（由申请人提供）：我寻求 K23 奖项的目标是调查 HIV 感染并在转化研究领域发展职业生涯。我的特别研究兴趣是确定有效的预防性或治疗性艾滋病疫苗所需的重要免疫反应。我组建了一个指导委员会，由在转化研究方面拥有良好记录的国际知名科学家组成；我将获得临床研究方法学方面的培训以及免疫学方法学方面的额外实验室培训；我建议开展一系列指导研究项目，这些项目将为我提供获得成为一名富有成效的独立临床研究员所需的“实践”培训的机会。 尽管接受了抗逆转录病毒治疗，许多艾滋病毒感染者的艾滋病毒病毒复制水平仍然较低。这种病毒血症代表复制能力降低的耐药病毒。这些患者的 CD4+ T 细胞计数保持增加。然而，这些患者中很大一部分最终会出现高水平病毒血症。我感兴趣的是研究可预测哪些患者可能出现高水平病毒血症的免疫学参数，以及研究耐药病毒血症对整个免疫系统的影响。我提出以下具体目标：（1）评估较高的 HIV 特异性 CD4+ 和 CD8+ T 细胞反应是否与接受抗逆转录病毒治疗的患者控制耐药 HIV 复制有关； (2) 评估抗逆转录病毒治疗病毒血症部分控制的患者中免疫系统老化的证据是否与 CD4+ T 细胞丧失相关； (3) 评估接受抗逆转录病毒治疗后病毒血症部分控制的患者中 T 细胞对免疫反应的能力是否发生改变。我们假设，维持高水平的 HIV 特异性 T 细胞反应将预测维持对病毒血症的部分控制；我们将纵向跟踪这些患者，对 HIV 特异性 T 细胞功能进行系列测量。此外，部分 HIV 病毒血症的存在与效应 CD4+ T 细胞比例的增加有关，这是免疫系统老化的标志。我们假设这些患者将持续丧失 CD4+ T 细胞；我们将跟踪他们进行 T 细胞免疫表型分析的系列测量。此外，我们假设病毒血症部分控制的患者对免疫反应的反应会降低，这是对体内免疫能力的估计。对于目标 1 和 2，我将使用在已建立的队列研究中收集的样本。对于目标3，我将进行一项前瞻性介入研究，其中我将设计并实施一个独立的临床研究项目。