Basic and Applied Studies in Development of an AIDS Vaccine

艾滋病疫苗开发的基础与应用研究

• 批准号: 6433034
• 负责人: Marjorie Robert-Guroff
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6433034
• 关键词: AIDS vaccines; HIV envelope protein gp120; Macaca mulatta; Pan; T lymphocyte; antiviral antibody; cellular immunity; dosage; drug design /synthesis /production; human immunodeficiency virus 1; human immunodeficiency virus 2; human tissue; humoral immunity; macrophage; mucosal immunity; recombinant virus; simian immunodeficiency virus; vaccine development; vector vaccine; virus envelope; virus infection mechanism; virus receptors

A combination vaccine approach utilizing adenovirus-HIV or SIV-recombinants to prime immune responses followed by boosting with subunit protein elicits humoral, cellular, and mucosal immune responses in non-human primates. Significant protection against infection and/or disease progression has been demonstrated in chimpanzee and macaque models. These results have provided the basis for moving the strategy forward into human phase I trials. To further develop the approach, mutational analyses have been performed to identify deleterious sequences while preserving immunogenic epitopes in target genes. New adenovirus recombinants have been constructed and a broader spectrum of HIV and SIV structural, regulatory, and auxilliary genes are being incorporated into the adenovirus vectors. These will be assessed in appropriate animal models in combination with DNA immunizations for synergistic priming. The booster subunit immunogen has also been a focus of investigations. A novel, synthetic peptide polymer (peptomer) representing the binding site for CD4 on the viral envelope, mimics the native structure of the protein. As the peptomer contains CTL, T-helper, and conformational B-cell epitopes, it should elicit good immunity and exhibit protective efficacy against a broad spectrum of viral isolates. Evaluation of an SIV peptomer in macaques has shown that it is very immunogenic but not protective. Viral isolates which emerged following the challenge exposure were CD4 independent, suggesting immune selection of viral escape mutants. Further studies will be necessary to determine if the CD4 binding domain of the envelope should be eliminated from vaccine preparations, or if the strategy will prove effective in the HIV system, which is less prone to development of CD4 independent isolates. Finally, an effective vaccine must prevent sexual transmission of HIV, and studies have focused on protective immune responses at mucosal sites. Natural resistance in a macaque has been shown to result from viral-specific cellular immunity acquired following previous mucosal SIV exposures which did not result in infection. The mechanism responsible for the initial resistance appears to involve regulation of CCR5 expression on the surface of macaque CD4+ T cells following viral infection, resulting in a failure of viral amplification. These studies have also pointed to the lamina propria of the intestine as a potential viral reservoir. AIDS title: Adenovirus-Recombinant/Subunit Protein Vaccines for AIDS.

利用腺病毒-HIV或SIV重组体引发免疫反应，然后用亚单位蛋白加强的联合疫苗方法在非人灵长类动物中引发体液、细胞和粘膜免疫反应。 在黑猩猩和猕猴模型中已经证明了对感染和/或疾病进展的显著保护。这些结果为将该策略推进到人体I期试验提供了基础。为了进一步开发该方法，已经进行了突变分析以鉴定有害序列，同时保留靶基因中的免疫原性表位。 已经构建了新的腺病毒重组体，并且将更广泛的HIV和SIV结构、调节和辅助基因并入腺病毒载体中。 这些将在适当的动物模型中与DNA免疫结合进行评估，以获得协同引发。加强亚单位免疫原也一直是研究的焦点。 一种新型的合成肽聚合物（peptomer）代表病毒包膜上的CD 4结合位点，模拟蛋白质的天然结构。 由于肽异构体含有CTL、辅助性T细胞和构象B细胞表位，因此它应该引起良好的免疫力，并表现出对广谱病毒分离株的保护功效。 在猕猴中对SIV肽聚体的评估表明，它具有很强的免疫原性，但没有保护性。 攻击暴露后出现的病毒分离株是CD 4非依赖性的，表明病毒逃逸突变体的免疫选择。 进一步的研究将是必要的，以确定是否应该从疫苗制剂中消除包膜的CD 4结合结构域，或者该策略是否将证明在HIV系统中有效，这是不太容易发展的CD 4非依赖性分离株。 最后，有效的疫苗必须防止艾滋病毒的性传播，研究集中在粘膜部位的保护性免疫反应。 猕猴的自然抵抗力已被证明是由先前粘膜SIV暴露后获得的病毒特异性细胞免疫引起的，这些粘膜SIV暴露未导致感染。 负责初始抗性的机制似乎涉及在病毒感染后调节猕猴CD 4 + T细胞表面上的CCR 5表达，导致病毒扩增失败。 这些研究还指出，肠道固有层是潜在的病毒储存库。 艾滋病标题：艾滋病腺病毒重组/亚单位蛋白疫苗。