Induction of HIV-specific Immune Responses

诱导 HIV 特异性免疫反应

基本信息

批准号：
7161377
负责人：
RAJESH T GANDHI
金额：
$ 63.06万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-01-01 至 2010-12-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Virus-specific CD4 and CD8 T cell responses are important in controlling HIV replication, but in most infected individuals these responses are inadequate to fully contain the virus. Emerging data indicate that there is a functional loss in cellular immune responses as HIV disease progresses, suggesting that efforts to augment immunity may provide a therapeutic benefit. Dendritic cells (DCs) are the most potent antigen presenting cells, and when manipulated ex vivo to express viral antigens these cells can efficiently boost T cell responses in humans after re-injection. One of the most promising methods of delivering antigen to DCs is by transfection with mRNA encoding specific immunogens, which has been shown in human cancer studies to induce CD4 and CD8 responses to those antigens. This new method allows delivery of autologous HIV sequences to DCs, which may provide a unique advantage in augmenting virus-specific immune responses in an infected individual. Thus, we believe that vaccination with DCs transfected with autologous HIV mRNA is a promising approach to immune-based therapy. Our specific aims in this proposal are to: 1) Define the optimal method of delivering autologous HIV antigens to DCs to elicit strong and diverse virus-specific CD4 and CD8 immune responses. This work will focus on mechanisms of antigen presentation, including issues of immune interference, the effect of subcellular compartmentalization of antigen on immunogenicity and the effect of a costimulatory molecule, OX40 ligand, on DC function; 2) Clone autologous HIV mRNA transcripts from infected individuals with suppressed virus loads for transfection into DCs; and 3) Test the safety, immunogenicity and antiviral effect of this method of inducing immune responses against autologous HIV antigens by conducting a clinical trial of mRNA-transfected DCs in HIV+ subjects who have suppressed virus loads on antiretroviral therapy. Relevance of this research to public health: This work will lead to a better understanding of how to boost immune responses against HIV using a new method of vaccination. By understanding the mechanisms by which immune responses against HIV can be augmented, this may lead to improved ways of treating this disease and may help in developing a vaccine to prevent this infection.

描述（由申请人提供）：病毒特异性 CD4 和 CD8 T 细胞反应对于控制 HIV 复制很重要，但在大多数感染个体中，这些反应不足以完全遏制病毒。新数据表明，随着艾滋病毒疾病的进展，细胞免疫反应的功能丧失，这表明增强免疫力的努力可能会带来治疗益处。树突状细胞 (DC) 是最有效的抗原呈递细胞，当离体操作以表达病毒抗原时，这些细胞可以在重新注射后有效增强人体的 T 细胞反应。将抗原递送至 DC 的最有前途的方法之一是用编码特定免疫原的 mRNA 转染，人类癌症研究已表明这种方法可诱导针对这些抗原的 CD4 和 CD8 反应。这种新方法允许将自体 HIV 序列递送至 DC，这可能为增强感染个体的病毒特异性免疫反应提供独特的优势。因此，我们相信用自体 HIV mRNA 转染的 DC 进行疫苗接种是一种有前途的免疫治疗方法。我们在该提案中的具体目标是：1) 定义将自体 HIV 抗原递送至 DC 的最佳方法，以引发强烈且多样化的病毒特异性 CD4 和 CD8 免疫反应。这项工作将重点关注抗原呈递机制，包括免疫干扰问题、抗原亚细胞区室化对免疫原性的影响以及共刺激分子 OX40 配体对 DC 功能的影响； 2) 从病毒载量受到抑制的感染个体中克隆自体 HIV mRNA 转录本，用于转染至 DC 中； 3) 通过在抗逆转录病毒治疗抑制病毒载量的 HIV+受试者中进行 mRNA 转染的 DC 临床试验，测试这种诱导针对自体 HIV 抗原的免疫应答的方法的安全性、免疫原性和抗病毒效果。这项研究与公共卫生的相关性：这项工作将有助于更好地了解如何使用新的疫苗接种方法增强针对艾滋病毒的免疫反应。通过了解增强针对艾滋病毒的免疫反应的机制，可能会改进治疗这种疾病的方法，并可能有助于开发预防这种感染的疫苗。