ANTI-HIV T CELL RESPONSES DURING ANTIVIRAL DRUG THERAPY

抗病毒药物治疗期间的抗 HIV T 细胞反应

• 批准号: 6373699
• 负责人: CHARLES R RINALDO
• 金额: $ 68.23万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-08-01 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6373699
• 关键词: AIDS therapy; HIV infections; T cell receptor; T lymphocyte; antiAIDS agent; apoptosis; bioengineering /biomedical engineering; cellular immunity; clinical research; combination chemotherapy; cytokine; dendritic cells; flow cytometry; human subject; human therapy evaluation; immunomodulators; microorganism immunology; virus protein

DESCRIPTION (from applicant's abstract): The long-term efficacy of combination antiretroviral therapy (ART) for control of human immunodeficiency virus 1 (HIV-1) infection may depend on augmentation of anti-HIV-1 CD8+ or CD4+ T cell responses. We have shown that combination ART does not result in sustained enhancement of anti-HIV-1 CD8+ or CD4+ T cell reactivity in HIV-1 infected patients with advanced immunodeficiency. However, there is still a substantial population of CD8+ T cells that bind HLA class I / HIV-1 peptide tetramers in these patients, and repetitive stimulations of peripheral blood mononuclear cells from HIV-1 positive and negative individuals with dendritic cells (DCs) loaded with liposome-complexed HIV-1 proteins can induce secondary and primary CD8+ T cell responses to HIV-1 antigens. We also found that HIV-1 sequence changes can identify the nature of evolutionary forces shaping the post-ART response as well as identifying potential candidates for modifying T-cell responses. We therefore hypothesize that there are functionally competent T cells specific for HIV-1 in ART patients that are strongly influenced by changes in HIV-1 epitope sequences recognized by T cells. Based on these findings, we have formed a team of experts in DC/ T cell immunology, flow cytometric phenotyping, HIV-1 biology and genetics, vector engineering, in vitro cell imaging and HLA typing to examine the boosting of anti-HIV-1 T cell responses by DCs. In Aim #1 we propose to deliver HIV-1 proteins and whole virus bound to particulates, and apoptotic bodies derived from autologous CD4+ T cells infected with lab strain and autologous virus, and characterize various important aspects of their ability to present antigen to T cells. These DCs will be treated with cytokines, chemokines and anti-apoptotic agents to boost their T cell stimulatory abilities. In aim #2, we will identify and characterize virus evolutionary changes prior to and following combination ART with emphasis on a near full spectrum of CD8+ T cell epitopes. In aim #3, we will determine the fine-specificity and breadth of the T cell responses elicited by the engineered DCs based on antigen delivery systems developed in Aim #1 and the HIV-1 sequences derived in Aim#2. We believe that these new, novel antigen delivery systems and processing methods will be highly efficient at inducing a broad spectrum of anti-HIV-1 T cell responses in ART patients.

描述（来自申请人的摘要）：组合的长期功效 用于控制人类免疫缺陷病毒1的抗逆转录病毒疗法1 （HIV-1）感染可能取决于抗HIV-1 CD8+或CD4+ T细胞的增强 回答。我们已经表明，组合艺术不会导致持续 HIV-1感染HIV-1抗HIV-1 CD8+或CD4+ T细胞反应性的增强 晚期免疫缺陷患者。但是，仍然有很大的 结合HLA I / HIV-1类肽四聚体的CD8+ T细胞的种群 这些患者以及外周血单核的重复刺激 来自HIV-1阳性和阴性个体具有树突状细胞（DC）的细胞 装有脂质体的HIV-1蛋白可以诱导次要和初级 CD8+ T细胞对HIV-1抗原的反应。我们还发现HIV-1序列 变化可以确定塑造后艺术的进化力的性质 响应以及确定用于修改T细胞的潜在候选者 回答。因此，我们假设存在功能上的t 受HIV-1特有的细胞在受到强烈影响的ART患者中 T细胞识别的HIV-1表位序列的变化。基于这些 调查结果，我们组成了DC/ T细胞免疫学专家团队，流量 细胞术表型，HIV-1生物学和遗传学，矢量工程，在 体外细胞成像和HLA键入以检查抗HIV-1 T细胞的增强 DCS的响应。在AIM＃1中，我们建议提供HIV-1蛋白质和整个 与颗粒结合的病毒和源自自体CD4+的凋亡体 感染实验室菌株和自体病毒的T细胞，并表征各种 它们对T细胞呈抗原的能力的重要方面。这些DC 将用细胞因子，趋化因子和抗凋亡剂进行治疗以提升 他们的T细胞刺激能力。在AIM＃2中，我们将确定并 在组合艺术之前和之后的病毒进化变化表征 重点是几乎全光谱CD8+ T细胞表位。在AIM＃3中，我们 将确定T细胞响应的精细特异性和广度 基于在 AIM＃1和AIM＃2中得出的HIV-1序列。我们相信这些新的 新颖的抗原输送系统和加工方法将非常有效 在诱导ART患者中诱导广泛的抗HIV-1 T细胞反应。