Induction of HIV-specific Immune Responses

诱导 HIV 特异性免疫反应

• 批准号: 7750022
• 负责人: RAJESH T GANDHI
• 金额: $ 50.43万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7750022
• 关键词: Address; Antigen Presentation; Antigen-Presenting Cells; Antigens; Antiviral Agents; Autologous; CD8B1 gene; Cell physiology; Cells; Clinical Trials; Consensus Sequence; Data; Dendritic Cells; Disease; HIV; HIV Antigens; Human; Immune; Immune response; Immunity; In Vitro; Individual; Infection prevention; Injection of therapeutic agent; Lead; Malignant Neoplasms; Messenger RNA; Methods; Persons; Public Health; Research; T cell response; Techniques; Testing; Therapeutic; Transcript; Transfection; Vaccination; Vaccines; Viral Antigens; Viral load measurement; Virus; Work; antiretroviral therapy; base; design; functional loss; immunogenicity; improved; in vivo; response; safety study; safety testing; tumor necrosis factor ligand superfamily member 4; vaccine development

Virus-specific CD4 and CDST 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 CDSimmune 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 suppressedvirus 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.

病毒特异性 CD4 和 CDST 细胞反应对于控制 HIV 复制很重要，但在大多数感染者中 对于个人来说，这些反应不足以完全遏制病毒。新出现的数据表明，有一个 随着艾滋病毒疾病的进展，细胞免疫反应的功能丧失，这表明增强免疫反应的努力 免疫力可能提供治疗益处。树突状细胞 (DC) 是最有效的抗原呈递剂 细胞，当离体操作表达病毒抗原时，这些细胞可以有效增强 T 细胞 重新注射后人类的反应。将抗原递送至 DC 的最有前途的方法之一是 通过转染编码特定免疫原的 mRNA，这已在人类癌症研究中得到证实 诱导对这些抗原的 CD4 和 CD8 反应。这种新方法可以输送自体艾滋病毒 DC 序列，这可能在增强病毒特异性免疫反应方面提供独特的优势 在受感染的个体中。因此，我们认为用自体 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。我们在本提案中的具体目标是： 1) 定义 将自体 HIV 抗原递送至 DC 以引发强而多样的病毒特异性 CD4 的最佳方法 和 CDSimune 反应。这项工作将重点关注抗原呈递机制，包括问题 免疫干扰、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) 克隆自体HIV mRNA转录本 来自病毒载量受到抑制的感染个体，用于转染至 DC； 3）测试安全性， 这种诱导针对自体 HIV 的免疫反应的方法的免疫原性和抗病毒作用 通过在已抑制病毒的 HIV+ 受试者中进行 mRNA 转染 DC 的临床试验来获得抗原 抗逆转录病毒治疗的负担。 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促进 使用新的疫苗接种方法对抗艾滋病毒的免疫反应。通过了解机制 可以增强针对艾滋病毒的免疫反应，这可能会导致治疗这种疾病的方法得到改进 疾病，并可能有助于开发疫苗来预防这种感染。