Antigen Processing in HIV-infected Individuals

描述（由申请方提供）：CD 4 + T细胞依赖于抗原呈递细胞（ARC）活化。HIV+个体的ARC功能障碍可能加速或加剧CD 4 + T细胞功能障碍，并可能导致免疫缺陷水平升高。很少有研究涉及HIV感染对抗原加工和呈递的作用。文献显示了不同的结果，一些研究声称存在显著的ARC缺陷，而另一些研究则没有。这支持了我们的总体假设，即来自HIV感染者亚组的APC具有抗原加工和呈递缺陷。 我们已经从HLA转基因小鼠中开发了克隆的HLA I类和II类限制性T细胞杂交瘤，其容易识别由人APC呈递的微生物抗原。它们将用于测量来自HIV+个体的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+个体亚组的MN和DC是否在抗原加工和呈递中具有MHC I类、MHC II类或整体缺陷。将用HLA匹配的T杂交瘤研究来自HIV+患者和HIV对照的MN和DC中的APC功能。将使用初始人CD 4 + T细胞进行功能性共刺激试验。在已确定缺陷的患者中，将探索功能障碍的机制。 目标2.确定细胞因子（GM-CSF、IFN-γ或IFN-α）是否可以增强HIV+个体APC中的抗原加工和呈递。 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感染者的抗原加工过程对最佳疫苗开发具有重要意义。使免疫抗原最佳加工并呈递给T细胞对于细胞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提高疫苗的效力。这项工作可能对HIV免疫治疗领域产生重大影响。来自所提出的研究的数据可以给出使用细胞因子调节剂来增强APC功能从而增加T细胞应答的基本原理。 由于先前对HIV感染患者APC功能的研究因其对自体T细胞的依赖而复杂化（即可能存在HIV诱导的APC和T细胞缺陷），因此我们的研究将首次对HIV+和HIV-患者的APC功能进行良好对照的比较。

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.