Targeting gp41 to elicit neutralizing antibodies against HIV-1

描述（由申请人提供）：全球迫切需要开发一种针对HIV-1的保护性疫苗。中和抗体（nab）可以有效预防HIV-1感染。然而，诱导对许多抗原性不同的HIV-1分离株具有广泛反应性的nab一直是主要挑战，并且仍然是HIV-1疫苗开发的关键障碍。提出的研究的主要目的是产生能够在粘膜表面引起广泛反应性nab的新型抗原，长期目标是开发针对该病毒的疫苗。具体来说，我们提出了一种新的技术，通过产生在细胞表面表达抗原完整的gp41蛋白片段的重组乳酸菌（LAB）来靶向gp41的膜近端外区（MPER）。本提案的范围仅限于以下具体目的：(1)产生在细胞表面显示HIV-1 gp41 MPER的重组干酪乳杆菌，(2)设计最佳疫苗策略并评估重组干酪乳杆菌在小鼠中的免疫原性，(3)在XenoMouse中引发针对HIV-1 gp41 MPER的广泛反应性nab。这项研究的成功完成将产生新的候选疫苗和引发保护性体液免疫反应的策略，这将是艾滋病疫苗开发工作向前迈出的一大步。公共卫生相关性：本提案的主要目标是设计、生产和评估能够引发针对HIV-1（导致艾滋病的病毒）的有效免疫反应的候选疫苗。为了实现这些目标，我们正在采用一种新的方法来产生抗原，这种抗原可以引发病毒中和抗体，这种抗体在病毒进入的部位对许多不同的变体具有广泛的反应性。成功完成拟议的研究将克服艾滋病疫苗研制的一个关键障碍。

DESCRIPTION (provided by applicant): There is a global urgency to develop a protective vaccine against HIV-1. Neutralizing antibodies (Nabs) can provide effective prophylaxis against HIV-1 infections. However, eliciting Nabs that are broadly reactive against many antigenically diverse HIV-1 isolates has been a major challenge and it remains a critical roadblock to HIV-1 vaccine development. The primary objective of the studies being proposed is to generate novel antigens that are able to elicit broadly reactive Nabs on the mucosal surface, with a long-term goal of developing a vaccine against the virus. Specifically, we propose to target the membrane-proximal external region (MPER) of gp41 by generating recombinant lactic acid bacteria (LAB) that express antigenically intact gp41 protein fragments on the cell surface using a novel technology. The scope of this proposal is limited to the following specific aims: (1) to generate recombinant Lactobacillus casei that display HIV-1 gp41 MPER on the cell surface, (2) to devise an optimal vaccine strategy and to evaluate immunogenic properties of recombinant L. casei in mice, and (3) to elicit broadly reactive Nabs against HIV-1 gp41 MPER in XenoMouse. Successful completion of this study will generate novel vaccine candidates and strategies for eliciting protective humoral immune responses, which would represent a major step forward in AIDS vaccine development efforts. PUBLIC HEALTH RELEVANCE: The major goals of this proposal are to design, to generate and to evaluate vaccine candidates that can elicit potent immune responses against HIV-1, the virus that causes AIDS. Towards these goals, we are taking a novel approach of generating antigens that can elicit virus-neutralizing antibodies that are broadly reactive against many different variants at the site of virus entry. Successful completion of proposed studies will overcome a critical roadblock to AIDS vaccine development.