Antigen Processing in HIV-infected Individuals

HIV 感染者的抗原加工

• 批准号: 6892745
• 负责人: DAVID H CANADAY
• 金额: $ 22.95万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6892745
• 关键词: AIDS therapy; HIV infections; MHC class I antigen; MHC class II antigen; antigen presentation; antigen presenting cell; clinical research; cytokine; enzyme linked immunosorbent assay; flow cytometry; helper T lymphocyte; human subject; hybridomas; major histocompatibility complex; polymerase chain reaction

DESCRIPTION (provided by applicant): CD4+ T cells are dependent on antigen presenting cells (ARC) for their activation. ARC dysfunction in HIV+ individuals could accelerate or exacerbate CD4+ T cell dysfunction and may contribute to increased levels of immunodeficiency. Few studies have addressed the role of HIV infection on antigen processing and presentation. The literature has demonstrated disparate results with some studies claiming significant ARC defects and others none. This supports our overall hypothesis that APC from a subset of HIV-infected individuals have an antigen processing and presentation defect. We have developed clonal HLA class I and ll-restricted T cell hybridomas from HLA-transgenic mice that readily recognize microbial antigens presented by human APC. They will be used to measure antigen processing function in APC from HIV+ individuals. A functional costimulation assay will also be performed. Aim 1. To determine if MN and DC from a subset of HIV+ individuals have a MHC class I, MHC class II or global defect in antigen processing and presentation. APC function in MN and DC from HIV+ patients and HIV controls will be studied with HLA-matched T hybridomas. A functional costimulation assay will be performed with naive human CD4+ T cells. In patients with defects identified, mechanisms of the dysfunction will be explored. Aim 2. To determine if antigen processing and presentation in APC from HIV+ individuals can be enhanced by cytokines (GM-CSF, IFN-gamma, or IFN-alpha). Aim 3. To determine if antigen processing and presentation in APC from HIV+ individuals is improved after highly active antiretroviral therapy (HAART). An understanding of antigen processing in HIV-infected individuals has significance for optimal vaccine development. Having the immunizing antigen optimally processed and presented to T cells is important for both cellular and humoral immunity. Determining specific cytokines that boost antigen processing and costimulation could augment vaccine efficacy. This work could have significant ramifications to the field of immuno-therapy for HIV. Data from the proposed studies may give a rationale for using cytokine modulators to enhance APC function thereby increasing T cell responses. Since previous studies of APC function in HIV-infected patients were complicated by their dependence on autologous T cells (i.e. HIV-induced deficits in both APC and T cells were potentially present), our studies will provide the first well-controlled comparison of APC function in HIV+ and HIV- persons.

描述（由申请人提供）：CD4+ T 细胞的激活依赖于抗原呈递细胞 (ARC)。 HIV+ 个体的 ARC 功能障碍可能会加速或加剧 CD4+ T 细胞功能障碍，并可能导致免疫缺陷水平升高。很少有研究探讨 HIV 感染对抗原加工和呈递的作用。文献证明了不同的结果，一些研究声称存在显着的 ARC 缺陷，而另一些则没有。这支持了我们的总体假设，即来自 HIV 感染者子集的 APC 具有抗原加工和呈递缺陷。 我们已经从 HLA 转基因小鼠中开发出克隆性 HLA I 类和 II 类限制性 T 细胞杂交瘤，它们很容易识别人类 APC 呈递的微生物抗原。它们将用于测量 HIV+ 个体 APC 中的抗原处理功能。还将进行功能性共刺激测定。 目标 1. 确定来自 HIV+ 个体子集的 MN 和 DC 是否在抗原加工和呈递方面存在 MHC I 类、MHC II 类或整体缺陷。将使用 HLA 匹配的 T 杂交瘤研究 HIV+ 患者和 HIV 对照的 MN 和 DC 中的 APC 功能。将使用初始人类 CD4+ T 细胞进行功能性共刺激测定。在发现缺陷的患者中，将探讨功能障碍的机制。 目标 2. 确定 HIV+ 个体的 APC 中的抗原加工和呈递是否可以通过细胞因子（GM-CSF、IFN-γ 或 IFN-α）增强。 目标 3. 确定 HIV+ 个体的 APC 中的抗原加工和呈递在高效抗逆转录病毒治疗 (HAART) 后是否得到改善。 了解 HIV 感染者的抗原加工对于最佳疫苗开发具有重要意义。对免疫抗原进行最佳处理并呈递给 T 细胞对于细胞免疫和体液免疫都很重要。确定促进抗原加工和共刺激的特定细胞因子可以增强疫苗功效。这项工作可能会对艾滋病毒免疫治疗领域产生重大影响。拟议研究的数据可能为使用细胞因子调节剂增强 APC 功能从而增加 T 细胞反应提供了理论依据。 由于以前对 HIV 感染患者的 APC 功能的研究因他们对自体 T 细胞的依赖而变得复杂（即可能存在 HIV 诱导的 APC 和 T 细胞缺陷），因此我们的研究将提供第一个 APC 功能的良好对照比较HIV+ 和 HIV- 人群。