Induction of HIV-specific Immune Responses

病毒特异性的CD4和CDST细胞反应在控制艾滋病毒复制方面很重要，但在大多数感染者中 个人这些反应不足以完全遏制病毒。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，这表明加强 免疫可能会带来治疗上的好处。树突状细胞(DC)是最有效的抗原提呈细胞。 细胞，当在体外操纵这些细胞表达病毒抗原时，这些细胞可以有效地促进T细胞 重新注射后人体的反应。向DC递送抗原的最有前途的方法之一是 通过转导编码特定免疫原的信使核糖核酸，这已在人类癌症研究中显示出来 以诱导对这些抗原的CD4和CD8反应。这一新方法允许传递自体艾滋病毒 序列到DC，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 是一种很有前途的基于免疫的治疗方法。我们在这项建议中的具体目标是：1)界定 向树突状细胞递送自体HIV抗原以诱导强而多样的病毒特异性CD4的最佳方法 和CDS免疫反应。这项工作将侧重于抗原呈递的机制，包括 免疫干扰的研究，抗原亚细胞区隔对免疫原性的影响 共刺激分子OX40配体对树突状细胞功能的影响；2)克隆自体HIV mRNA转录本 来自病毒载量受抑制的感染者，用于转染DC；以及3)测试安全性， 诱导自体HIV免疫应答方法的免疫原性和抗病毒效果 在抑制病毒的HIV+受试者中进行基因转染树突状细胞的临床试验 大量的抗逆转录病毒治疗。 这项研究与公共卫生的相关性：这项工作将使人们更好地理解如何促进 使用一种新的疫苗接种方法对艾滋病毒的免疫反应。通过了解这些机制， 哪些针对HIV的免疫反应可以被增强，这可能导致改进治疗方法 这可能有助于开发一种疫苗来预防这种感染。

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.