VLP VACCINES FOR HIV PREVENTION

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 一种预防性的HIV-1疫苗应该会引起广泛的交叉反应中和活性。天然病毒粒子上的gp120-gp41包膜蛋白是诱导中和抗体的主要靶点。虽然Env的一些特性使其很难获得广泛的中和抗体，但近年来通过改变其结构、采用新的递送平台和联合给予佐剂来增强Env的免疫力方面取得了进展。 病毒样颗粒(VLP)的使用已显示出作为一种新的疫苗平台的巨大潜力。最近的研究还表明，较低效价的中和抗体可以保护猕猴免受低剂量重复的粘膜SIV攻击，这种攻击模仿了性接触对人类的感染。 最近，我们开发了新的方法来制备富含Env的嵌合HIV VLP(CVLP)，并发现这种含有膜锚定形式的鞭毛蛋白或可变区截短的鞭毛蛋白作为佐剂的cVLP可诱导高水平的系统和粘膜HIV特异性抗体应答，并具有更广泛的中和活性。我们的研究正在检验这样一个假设，即抗原和佐剂在同一颗粒结构中的存在将通过将这两种成分同时递送到相同的抗原提呈细胞来产生有效的艾滋病毒疫苗抗原。 天然状态的Env抗原递呈与膜锚定佐剂和粘膜递送相结合，为激发针对HIV的强大NAB反应提供了一种有前景的方法，旨在阻断感染过程的初始步骤。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. A prophylactic HIV-1 vaccine should elicit broadly cross-reactive neutralizing activity. The gp120-gp41 Env protein on the native virion is the primary target for eliciting neutralizing antibodies. Although several features of Env make it difficult to elicit broadly neutralizing antibodies, progress has been achieved in recent years in enhancing the immunity of Env by modifying its structure, employing novel delivery platforms, and co-administration of adjuvants. The use of virus-like particles (VLPs) has shown great potential as a new vaccine platform. Recent studies have also demonstrated that lower titers of neutralizing antibody can protect against low-dose repeated mucosal SHIV challenge in macaques, which mimics infection of humans by sexual contact. Recently we developed novel approaches to produce Env-enriched chimeric HIV VLPs (cVLPs) and found that such cVLPs containing a membrane-anchored form of flagellin or a variable-region truncated flagellin as adjuvants induced high levels of systemic and mucosal HIV specific antibody responses, with broadened neutralizing activity. Our research is testing the hypothesis that the presence of antigen and adjuvant in the same particulate structure will generate an effective HIV vaccine antigen, by delivering both components simultaneously to the same antigen-presenting cells. The combination of Env antigen presentation in its native state combined with a membrane-anchored adjuvant and mucosal delivery provides a promising approach to stimulate strong nAb response against HIV, designed to block the initial step in the infection process.