CpG DNA:Epitope Fusion Peptide Conjugates as HIV Vaccine

CpG DNA：表位融合肽缀合物作为 HIV 疫苗

• 批准号: 6944109
• 负责人: Don J Diamond
• 金额: $ 21.5万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6944109
• 关键词: AIDS vaccines; CpG islands; HIV infections; Poxviridae; biotechnology; chemical structure function; flow cytometry; gene expression; genetically modified animals; helper T lymphocyte; host organism interaction; immunoconjugates; laboratory mouse; oligonucleotides; synthetic peptide; vaccine development; vaccine evaluation; vaccinia virus; AIDS vaccines; CpG islands; HIV infections; Poxviridae; biotechnology; chemical structure function; flow cytometry; gene expression; genetically modified animals; helper T lymphocyte; host organism interaction; immunoconjugates; laboratory mouse; oligonucleotides; synthetic peptide; vaccine development; vaccine evaluation; vaccinia virus

DESCRIPTION (provided by applicant): An effective vaccine against HIV infection remains an elusive goal, especially as the sequence diversity of the virus continues to expand. We developed a model system that relies on the recognition of T cell epitopes from immunodominant antigens of HIV to explore novel uses of oligodeoxynucleotides (ODN) as adjuvants, with the purpose of developing an improved strategy for vaccine delivery. We increased the sensitivity of our approach, by developing a novel synthetic chemical strategy of covalently modifying T-help/CTL epitope fusion peptides with CpG-ODN motifs. In this revised application, specific concerns of the Study Section have been addressed in preliminary data including the necessity for a T-help epitope, the fate of epitopes in the middle of peptide strings, and the evaluation of human-specific CpG-ODN. Immunogenicity, in vitro recognition of HIV-infected T cells, and protection against viral infection using a surrogate virus (poxvirus) will be criteria to measure efficacy of newly derived CpG-ODN:peptide conjugates in HLA transgenic murine models. The focus of the experimental section will be on strategies that yield greater sensitivity of immune stimulation by the conjugate vaccines, as well as broadness and strength of immune responses to epitopes from multiple antigens. The methodology for conjugating peptide to CpG-ODN will be intensively investigated in Specific Aim 1, with the purpose of disclosing new chemical structures that will heighten the sensitivity of immune response to the vaccine. A more focused ranking formula that distinguishes vaccines targeting acute and chronic HIV infection will be instituted. Since HIV has immense capacity for escape from cellular immunity, we will seek to combine epitopes from multiple antigens to prevent escape from immune recognition by HIV. In Specific Aim 2, we will explore protection models to assess whether the synthetic vaccine strategies that are most immunogenic in Specific Aim 1, also are more efficient at providing protection against an HIV-antigen recombinant poxvirus challenge. These will include more virulent forms of vaccinia virus, whose clearance may closely model outcomes of human viral infection with un-attenuated viruses. In addition, we will explore whether increased efficiency of immune recognition by CpG-ODN:peptide conjugates will also apply to HIV strains including clades A-D in direct lytic assays of HIV-infected Jurkat T cells. These studies will establish feasibility and provide impetus to extend these observations into primate models of HIV infection, and will justify the intensive studies proposed in this application.

描述（由申请人提供）：针对HIV感染的有效疫苗仍然是一个难以捉摸的目标，尤其是随着病毒的序列多样性不断扩展。我们开发了一个模型系统，该模型系统依赖于HIV免疫主导抗原的T细胞表位，以探索寡脱氧核苷酸（ODN）作为辅助的新颖用途，目的是制定改进的疫苗输送策略。我们通过开发一种新型的合成化学策略来增强方法的敏感性，该策略是通过CPG-ODN基序共价修饰T-螺旋/CTL表位融合肽。在此修订后的应用中，初步数据中已经解决了研究部分的具体问题，包括对T-螺旋表位的必要性，肽串中间的表位的命运以及对人类特异性CPG-ODN的评估。免疫原性，对感染HIV的T细胞的体外识别以及使用替代病毒（Poxvirus）的病毒感染的保护将是测量新衍生的CPG-ODN的功效的标准：HLA转基因鼠模型中的肽结合物。实验部分的重点将放在策略上，这些策略会产生偶联疫苗对免疫刺激的敏感性，以及对多种抗原表位的免疫反应的广泛性和强度。将肽与CpG-ODN结合的方法将在特定目标1中进行深入研究，目的是披露新的化学结构，以增强免疫反应对疫苗的敏感性。将建立一个更集中的排名公式，该公式将构建针对急性和慢性艾滋病毒感染的疫苗。由于HIV具有巨大的逃避细胞免疫力的能力，因此我们将寻求将多种抗原的表位结合起来，以防止HIV免疫识别。在特定的目标2中，我们将探索保护模型，以评估特定目标中最免疫原性的合成疫苗策略是否在提供针对HIV-抗原重组的POXVIRUS挑战方面更有效。这些将包括更具毒性形式的离甲酸病毒，其清除可能与未衰减病毒对人类病毒感染的结局进行密切模型。此外，我们将探索CpG-ODN：肽结合物的免疫识别效率是否也将适用于HIV菌株，包括在HIV感染的Jurkat T细胞的直接裂解测定中，包括A-D的A-D。这些研究将确定可行性并提供动力，将这些观察结果扩展到艾滋病毒感染的灵长类动物模型，并证明本应用程序中提出的强化研究是合理的。