Induction of HIV-specific Immune Responses

描述（由申请人提供）：病毒特异性CD4和CD8 T细胞反应在控制HIV复制中很重要，但在大多数感染个体中，这些反应不足以完全控制病毒。新出现的数据表明，随着艾滋病毒疾病的进展，细胞免疫反应存在功能丧失，这表明增强免疫的努力可能提供治疗益处。树突状细胞（dc）是最有效的抗原呈递细胞，当在体外操纵表达病毒抗原时，这些细胞可以在再次注射后有效地增强人体T细胞反应。将抗原传递到dc的最有希望的方法之一是转染编码特异性免疫原的mRNA，这在人类癌症研究中已被证明可以诱导CD4和CD8对这些抗原的反应。这种新方法允许将自体HIV序列传递到dc，这可能在增强受感染个体的病毒特异性免疫反应方面提供独特的优势。因此，我们相信用转染了自体HIV mRNA的dc接种疫苗是一种很有前途的免疫治疗方法。我们的具体目标是：1)确定将自体HIV抗原递送到dc的最佳方法，以引发强烈和多样化的病毒特异性CD4和CD8免疫反应。这项工作将集中于抗原呈递的机制，包括免疫干扰问题，抗原亚细胞区隔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)从抑制病毒载量的感染个体中克隆自身HIV mRNA转录物，转染到DCs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dc的临床试验，验证该方法诱导针对自身HIV抗原的免疫应答的安全性、免疫原性和抗病毒效果。这项研究与公共卫生的相关性：这项工作将使人们更好地了解如何使用一种新的疫苗接种方法来增强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，这可能导致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。

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.