Basic and Applied Studies in Development of an AIDS Vaccine

一种联合疫苗方法使用腺病毒-HIV或SIV-重组体来启动免疫应答，随后用亚单位蛋白加强免疫，在非人类灵长类动物中诱导体液、细胞和粘膜免疫应答。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类第一阶段试验提供了基础。为了进一步发展这种方法，已经进行了突变分析，以识别有害序列，同时保留目标基因中的免疫原性表位。新的重组腺病毒已经构建，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进行评估，并结合DNA免疫进行协同启动。加强亚单位免疫原也一直是研究的重点。一种新型的合成多肽聚合物(多肽)代表了病毒包膜上的CD4结合部位，模仿了蛋白质的天然结构。由于该肽含有CTL、辅助性T细胞和构象B细胞表位，它应该能诱导良好的免疫力，并对广泛的病毒分离株表现出保护作用。对猕猴SIV喷雾剂的评估表明，它具有很强的免疫原性，但不具有保护性。在挑战暴露后出现的病毒分离株是不依赖于CD4的，这表明对病毒逃逸突变的免疫选择。将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，或者该策略是否在HIV系统中被证明是有效的，因为HIV系统不太容易发展成CD4独立的分离株。最后，一种有效的疫苗必须防止艾滋病毒的性传播，研究的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于先前接触SIV黏膜后获得的病毒特异性细胞免疫所致，但并未导致感染。最初耐药的机制似乎涉及到病毒感染后猕猴CD4T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，肠道的固有层是一个潜在的病毒宿主。艾滋病标题：艾滋病的腺病毒-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.