NOVEL VIRAL VECTORS FOR AIDS VACCINES

拟议研究的长期目标是开发一种安全， 有效和实用的人类免疫缺陷疫苗 HIV-1和HIV-2。尽管减毒病毒（例如，SIVdeltanef） 是目前公认的“黄金标准”的保护实验， 艾滋病的SIV猕猴模型，对这种最终安全性的担忧， 疫苗可能会抑制其广泛接受和使用。这些 人们的担忧促使我们考虑一种疫苗方法， 腺相关病毒（AAV）的不寻常的遗传和生物学特征， 非致病性细小病毒。人类中的AAV感染很常见， 无症状，与疾病无关。 在本文提出的研究中，我们将描述一种新的方法， 利用重组AAV（rAAV）载体的遗传免疫， 传递SIV和HIV基因。在前期工作中，我们已经做出了重要的 包装方法的突破，rAAV是一种实用的DNA递送 系统此外，我们已经证明，携带SIV gp 160的rAAV 基因可以在接种疫苗的小鼠中产生强烈的抗体反应。因此我们 现在正准备向前推进大规模的免疫原性， 在猕猴中的SIV/SHIV模型中的攻击试验。 在相关工作中，我们提出使用rAAV载体进行“逆转录”， 免疫”。这种方法的原理很简单。的工作所 Burton和其他人，我们知道广泛中和 HIV-1主要分离株在感染者中很少见， 通过免疫。因此，提供预先选择的 抗体基因作为被动或“反向”免疫的形式。为此 为了达到这个目的，rAAV将用于递送广泛代表 中和HIV-1抗体（如b12）。希望是如此之高 高水平的强效和强有力的抗体将被递送到 并将预防艾滋病毒感染的疫苗。

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.