Basic and Applied Studies in Development of an AIDS Vaccine

在非人灵长类动物中，利用腺病毒- hiv或siv -重组体启动免疫应答，然后用亚单位蛋白增强的联合疫苗方法可引起体液、细胞和粘膜免疫应答。在黑猩猩和猕猴模型中证明了对感染和/或疾病进展的显著保护作用。这些结果为将该策略推进人体I期试验提供了基础。为了进一步发展该方法，已经进行了突变分析，以识别有害序列，同时保留靶基因中的免疫原性表位。新的腺病毒重组体已经被构建，更广泛的HIV和SIV结构、调控和辅助基因正在被纳入腺病毒载体。这些将在适当的动物模型中进行评估，并结合DNA免疫进行协同启动。增强型亚单位免疫原也一直是研究的重点。一种新的合成肽聚合物（肽体）代表CD4在病毒包膜上的结合位点，模仿蛋白质的天然结构。由于肽体含有CTL、t辅助细胞和构象b细胞表位，它应该能引起良好的免疫力，并对广泛的病毒分离物表现出保护作用。在猕猴中对SIV酶体的评估表明，它具有很强的免疫原性，但没有保护作用。暴露于攻击后出现的病毒分离株是CD4独立的，表明病毒逃逸突变体的免疫选择。需要进一步的研究来确定包膜的CD4结合结构域是否应该从疫苗制剂中消除，或者该策略是否在HIV系统中被证明是有效的，因为HIV系统不太容易产生CD4独立的分离株。最后，一种有效的疫苗必须能防止HIV的性传播，研究集中在粘膜部位的保护性免疫反应上。猕猴的自然抗性已被证明是由于先前的粘膜SIV暴露（未导致感染）后获得的病毒特异性细胞免疫所致。最初耐药的机制似乎涉及病毒感染后猕猴CD4+ T细胞表面CCR5表达的调控，导致病毒扩增失败。这些研究也指出肠固有层是一个潜在的病毒储存库。艾滋病题目：艾滋病腺病毒重组/亚单位蛋白疫苗。

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.