Basic and Applied Studies in Development of an AIDS Vaccine

联合疫苗方法利用腺病毒-HIV 或 SIV 重组体来引发免疫反应，然后用亚基蛋白进行加强，从而在非人类灵长类动物中引发体液、细胞和粘膜免疫反应。 黑猩猩和猕猴模型已证明对感染和/或疾病进展有显着的保护作用。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，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构建，并且更广泛的 HIV 和 SIV 结构、调节和辅助基因正在被整合到腺病毒载体中。 这些将在适当的动物模型中结合 DNA 免疫进行评估，以实现协同启动。增强亚基免疫原也一直是研究的焦点。 一种新型合成肽聚合物（peptomer）代表病毒包膜上 CD4 的结合位点，模拟蛋白质的天然结构。 由于 peptomer 含有 CTL、T 辅助细胞和构象 B 细胞表位，因此它应能引发良好的免疫力，并对多种病毒分离株表现出保护功效。 对猕猴中 SIV 肽聚体的评估表明，它具有很强的免疫原性，但不具有保护性。 攻击暴露后出现的病毒分离株与 CD4 无关，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是否应该从疫苗制剂中消除包膜的 CD4 结合域，或者该策略是否会在 HIV 系统中证明有效，因为 HIV 系统不太容易产生 CD4 独立分离株。 最后，有效的疫苗必须防止艾滋病毒的性传播，研究重点是粘膜部位的保护性免疫反应。 猕猴的天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，但未导致感染。 造成最初耐药性的机制似乎涉及病毒感染后猕猴 CD4 T 细胞表面 CCR5 表达的调节，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库。 艾滋病标题：艾滋病腺病毒重组/亚基蛋白疫苗。

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.