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CD 4和CDST细胞反应在控制HIV复制中很重要，但在大多数感染者中， 这些反应不足以完全控制病毒。新出现的数据表明， 随着HIV疾病的进展，细胞免疫反应的功能丧失，这表明， 免疫力可以提供治疗益处。树突状细胞（Dendritic cells，DCs）是最强的抗原提呈细胞 细胞，并且当离体操纵以表达病毒抗原时，这些细胞可以有效地增强T细胞免疫应答。 在人类再次注射后的反应。将抗原递送至DC的最有前途的方法之一是 通过用编码特异性免疫原的mRNA转染，这已经在人类癌症研究中显示 以诱导针对这些抗原的CD 4和CD 8应答。这种新方法允许自体HIV 序列的DC，这可能提供了一个独特的优势，在增强病毒特异性免疫反应 在一个受感染的人身上。因此，我们认为，用自体HIV mRNA转染的DC接种， 是一种很有前途的免疫疗法。我们在本建议中的具体目标是：1）界定 一种将自体HIV抗原递送至DC以诱导强而多样的病毒特异性CD 4的最佳方法 和CD免疫反应。这项工作将集中在抗原呈递的机制，包括问题 的免疫干扰，抗原的亚细胞区室化对免疫原性的影响， 共刺激分子OX 40配体对DC功能影响; 2）克隆自体HIV mRNA转录物 来自病毒载量受到抑制的感染个体，用于转染到DC中;和3）测试安全性， 该方法诱导针对自体HIV免疫应答的免疫原性和抗病毒效果 通过在HIV阳性受试者中进行mRNA转染的DC的临床试验， 抗逆转录病毒治疗的负担 这项研究与公共卫生的相关性：这项工作将使人们更好地了解如何促进 使用一种新的疫苗接种方法对抗艾滋病毒的免疫反应。通过了解这些机制， 可以增强针对HIV的免疫反应，这可能会导致治疗这种疾病的方法得到改善。 这可能有助于开发预防这种感染的疫苗。