Antigen Processing in HIV-infected Individuals

描述(由申请人提供)：CD4+T细胞依赖于抗原提呈细胞(ARC)来激活。HIV+患者的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的增加。很少有研究涉及艾滋病毒感染对抗原处理和提呈的作用。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感染者亚群的APC存在抗原处理和提呈缺陷。 我们从人类白细胞抗原转基因小鼠那里获得了克隆性的人类白细胞抗原I类和11类限制性T细胞杂交瘤，这些杂交瘤能够识别人类APC呈递的微生物抗原。它们将被用来测量HIV+患者APC的抗原处理功能。还将进行功能性共刺激试验。 目的1.确定HIV+个体的MN和DC是否存在MHC I类、MHC II类或抗原处理和提呈的全局性缺陷。HIV+患者和HIV对照的MN和DC的APC功能将用人类白细胞抗原相合的T杂交瘤进行研究。一项功能性的共刺激试验将在人类幼稚的CD4+T细胞中进行。在发现缺陷的患者中，将探索功能障碍的机制。 目的2.确定细胞因子(GM-CSF、干扰素-γ或干扰素-α)是否能促进HIV阳性个体APC的抗原处理和提呈。 目的3.确定经高效抗逆转录病毒治疗(HAART)后HIV阳性患者APC的抗原处理和提呈功能是否得到改善。 了解HIV感染者体内的抗原处理过程对于优化疫苗开发具有重要意义。免疫抗原的最佳处理和呈递给T细胞对细胞免疫和体液免疫都很重要。确定促进抗原处理和共刺激的特定细胞因子可以增强疫苗效力。这项工作可能会对艾滋病毒免疫疗法领域产生重大影响。来自拟议研究的数据可能为使用细胞因子调节剂增强APC功能从而提高T细胞应答提供了理论基础。 由于以前对HIV感染者APC功能的研究因其对自体T细胞的依赖而变得复杂(即潜在存在HIV诱导的APC和T细胞缺陷)，我们的研究将首次对HIV+和HIV携带者的APC功能进行良好的对照比较。

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.