NOVEL VIRAL VECTORS FOR AIDS VACCINES

拟议研究的长期目标是开发一种安全的、 有效、实用的人类免疫缺陷疫苗 病毒(艾滋病毒-1和艾滋病毒-2)。尽管减毒病毒(如SIVdeltanef) 目前在保护实验中被接受的“黄金标准”是 艾滋病的SIV猕猴模型，担心这样的终极安全性 疫苗可能会抑制它们的广泛接受和使用。这些 担忧促使我们考虑一种利用 腺相关病毒(AAV)的异常遗传和生物学特征 非致病性细小病毒。AAV感染在人类中是很常见的，完全是 无症状的，与疾病无关的。 在这里提出的研究中，我们将描述一种新的方法来 利用重组AAV(RAAV)载体进行的基因免疫 传递SIV和HIV基因。在前期工作中，我们取得了重要进展。 包装方法的突破，使rAAV成为一种务实的DNA传递 系统。此外，我们还展示了携带SIV gp160的rAAV 基因可在免疫小鼠中产生较强的抗体反应。因此，我们 现在准备以大规模的免疫原性和 挑战SIV/SIV模型在猕猴身上的试验。 在相关工作中，我们提出了使用rAAV载体来进行反转 这种方法的基本原理很简单。来自 Burton和其他人，我们知道广泛中和的抗体 HIV-1主要分离株在感染者中很少见，而且很难诱导 通过免疫接种。因此，提供预先选定的 抗体基因(S)作为被动或“反向”免疫的形式。为了这个 目的：rAAV将被用来传递具有广泛代表性的基因 针对HIV-1的中和抗体(如B12)。希望是如此之高 有效和强大的抗体水平将被传递到 并将防止疫苗中的艾滋病毒感染。

The long term goal of the proposed research is to develop a safe, efficacious, and practical vaccine against the human immunodeficiency viruses (HIV-1 and HIV-2). Although attenuated viruses (e.g., SIVdeltanef) are the currently accepted "gold standard" in protection experiments in the SIV macaque model of AIDS, concerns about the ultimate safety of such vaccines will probably inhibit their widespread acceptance and use. These concerns have prompter us to consider a vaccine approach that exploits the unusual genetic and biologic features of adeno-associated virus (AAV), a non-pathogenic parvovirus. AAV infection in humans is common, entirely asymptomatic, and not associated with disease. In the research proposed herein, we will characterize a novel approach to genetic immunization that exploits recombinant AAV (rAAV) vectors to deliver SIV and HIV genes. In preliminary work, we have made important breakthroughs in packaging methodology that rAAV a pragmatic DNA delivery system. In addition, we have demonstrated that rAAV carrying the SIV gp160 gene can engender a strong antibody response in vaccinated mice. Thus, we are now poised to move forwards with large-scale immunogenicity and challenge trials in the SIV/SHIV model in macaques. In related work, we propose to use rAAV vectors to perform "reverse immunization". The rationale for this approach is simple. From the work of Burton and others, we known that antibodies which broadly neutralize primary HIV-1 isolate are rare in infected humans, and difficult to elicit by immunization. Thus, it might make sense to deliver pre-selected antibody gene(s) as a form of passive or "reverse" immunization. For this purpose, rAAV will be used to deliver genes representing broadly neutralizing antibodies against HIV-1 (like b12). The hope is that high levels of potent and robust antibodies will be delivered to the circulation and will prevent HIV infection in vaccines.