Induction of HIV-specific Immune Responses

描述（由申请人提供）：病毒特异性CD 4和CD 8 T细胞应答在控制HIV复制方面很重要，但在大多数感染个体中，这些应答不足以完全遏制病毒。新出现的数据表明，随着艾滋病毒疾病的进展，细胞免疫应答功能丧失，这表明增强免疫力的努力可能会提供治疗益处。树突状细胞（DC）是最有效的抗原呈递细胞，并且当离体操纵以表达病毒抗原时，这些细胞可以在重新注射后有效地增强人体中的T细胞应答。将抗原递送至DC的最有希望的方法之一是通过用编码特异性免疫原的mRNA转染，其已在人类癌症研究中显示诱导对这些抗原的CD 4和CD 8应答。这种新方法允许将自体HIV序列递送到DC，这可能在增强感染个体的病毒特异性免疫应答方面提供独特的优势。因此，我们认为，用自体HIV mRNA转染的DC接种疫苗是一种有前途的基于免疫的治疗方法。我们在这项提案中的具体目标是：1）定义将自体HIV抗原递送至DC以引发强且多样的病毒特异性CD 4和CD 8免疫应答的最佳方法。本研究将重点探讨抗原提呈的机制，包括免疫干扰、抗原亚细胞区室化对免疫原性的影响以及共刺激分子OX 40配体对DC功能的影响; 2）从抑制病毒载量的感染者中克隆自体HIV mRNA转录本，转染DC;和3）通过在抗逆转录病毒治疗中抑制病毒载量的HIV+受试者中进行mRNA转染的DC的临床试验，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：这项工作将使人们更好地了解如何使用新的疫苗接种方法来增强对艾滋病毒的免疫反应。通过了解可以增强对HIV的免疫反应的机制，这可能会导致治疗这种疾病的方法得到改进，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.