Oral Delivery of Nanoparticles encapsulated with HIV-DNA Vaccine

描述（由申请人提供）：开发艾滋病毒疫苗是控制艾滋病流行的唯一希望。然而，尽管细胞介导的免疫（CMI）应答已被证明对于控制感染者中的病毒是重要的，但是可以诱导这些应答的疫苗的鉴定和成功仍然是难以捉摸的。DNA疫苗诱导CMI应答的能力及其安全性使质粒DNA成为传统疫苗的一个有吸引力的替代品。然而，尽管通过肌内途径的基于DNA的免疫取得了一些成功，但它显示出较差的免疫原性，特别是在非人灵长类动物和人类中。最近的研究强调了肠粘膜作为HIV感染的主要部位，因此疫苗策略应旨在诱导粘膜免疫。因此，我们预计口服DNA疫苗将是预防艾滋病毒的最有效方法。本项目提出了两个具体目标。在第一个目标中，我们将制作和表征目标特异性聚（丙交酯-共-乙交酯）（PLGA）纳米粒子封装与广谱猴-HIV（SHIV）DNA疫苗，然后筛选HIV-1蛋白在细胞培养中的表达。这将允许鉴定用于在小鼠中口服递送DNA疫苗的活基因递送载体。在第二个目标中，我们将研究口服纳米颗粒在胃肠道APC中表达基因的能力，然后测试小鼠对SHIV-DNA疫苗产生的免疫应答。我们预期，这种方法将强烈地产生粘膜和全身免疫应答与一个相对小剂量的DNA疫苗的单次口服免疫。这项提案的长期目标是开发DNA疫苗封装的纳米颗粒，作为一种有效的口服疫苗接种策略，对艾滋病毒感染。公共卫生相关性：拟议的研究将加强目前的努力，以开发一种有效的预防艾滋病毒的疫苗，控制艾滋病流行的唯一希望，从而直接解决国家卫生研究院的目标，通过多学科的努力，以改善人类健康，以预防传染病。

DESCRIPTION (provided by applicant): Development of a vaccine against HIV is the only hope of controlling the AIDS pandemic. However, although cell mediated immune (CMI) responses have been shown to be important for controlling the virus in infected persons, identification and success of a vaccine that could induce these responses has remained elusive. The ability of DNA vaccine to elicit CMI response and its safe profile makes plasmid DNA an attractive alternative to traditional vaccines. However, despite some success of DNA based immunization through intramuscular route, it shows poor immunogenicity especially in nonhuman primates & humans. Recent studies have highlighted the intestinal mucosa as the primary site of HIV-infection and therefore vaccine strategies should be aimed at induction of mucosal immunity. We expect that oral DNA vaccination will, thus, be the most effective approach in providing protection against HIV. Two specific aims are proposed in this project. In the first aim we will fabricate and characterize target specific poly (lactide-co-glycolide) (PLGA) nanoparticles encapsulated with broad spectrum simian-HIV (SHIV) DNA vaccine followed by screening for the expression of HIV-1 proteins in cell culture. This will allow identification of viable gene delivery vector(s) for oral delivery of DNA vaccine in mice. In the second aim we will investigate the ability of the orally administered nanoparticles to express genes in the APCs of gastrointestinal tract and then test the immune responses generated against the SHIV-DNA vaccine in mice. We expect that this approach will strongly generate both mucosal and systemic immune responses with a single oral immunization of a relatively small dose of DNA vaccine. The long term goal of this proposal is to develop DNA vaccine encapsulated nanoparticles, as an effective oral vaccination strategy against HIV-infection. PUBLIC HEALTH RELEVANCE: The proposed research will augment current efforts to develop an effective prophylactic vaccine against HIV, the only hope of controlling the AIDS pandemic, thus, directly addressing the goals of the NIH for improving human health through a multidisciplinary effort to prevent infectious disease.