Novel gp41 Immunogens for HIV-1 Vaccines

描述(申请人提供)：临床试验表明，HIV-1感染不能通过自然产生的病毒包膜(Env)蛋白免疫来预防。然而，很明显，env含有能够诱导广泛中和抗体的表位。现在的工作重点是如何修改HIV-1环境病毒，以提高其诱导中和抗体的能力。 HIV-1env是一种跨膜糖蛋白。Gp41的膜-近端外区含有似乎与膜脂相互作用的中和表位。这些表位是从感染患者身上分离出的三种单抗(称为2F5、4E10和Z13)的靶标。 这些抗体对HIV-1具有广泛的交叉中和活性，并似乎通过与多肽表位和膜脂相互作用发挥作用。因此，在设计HIV-1疫苗的免疫原时，考虑这些膜相互作用是重要的。解决这个问题的一种实验方法是将表位放置在病毒样脂蛋白颗粒(VLP)的膜附近。 根据文献描述的乙肝表面抗原(HBs)作为VLP和免疫原的用途，我们推测它将作为HIV-1 env蛋白膜近端外区广谱中和表位的合适载体分子。 在这个第一阶段的SBIR方案中，我们建议创建HIV来源的表位序列的几个变体，将其与HBs Ag VLP部分融合，以便能够识别最有效的免疫原。评估蛋白质免疫原性的唯一方法是免疫，首先在小动物模型中进行，然后进行临床试验。 本第一阶段提案的具体目标如下。 -特定目的#1：将HIV-1 env gp41表位插入到乙肝表面抗原中。 -特定目标2：评估嵌合HIV-HBs Ag颗粒的分泌物和抗原性。 -特定目标#3：评估嵌合HIV-HBs Ag颗粒的免疫原性。

DESCRIPTION (provided by applicant): Clinical trials have shown that HIV-1 infection cannot be prevented by immunization with naturally occurring viral envelope (Env) proteins. However, it is clear that Env contains epitopes that can induce broadly neutralizing antibodies. Efforts are now focused on ways to modify the HIV-1 Env to improve its ability to induce neutralizing antibodies. The HIV-1 Env is a transmembrane glycoprotein. The membrane-proximal external region of gp41 contains neutralizing epitopes that appear to interact with membrane lipids. These epitopes are the target of three monoclonal antibodies (called 2F5, 4E10, and Z13) that have been isolated from infected patients. These antibodies possess broad cross-neutralization activity against HIV-1 and appear to function by interaction with the peptide epitope and membrane lipids. It is therefore important to consider these membrane interactions in the design of immunogens for vaccines to HIV-1. One experimental approach to this problem is to position the epitopes in proximity to the membrane of a virus-like lipoprotein particle (VLP). Based on the literature describing the use of the hepatitis B surface antigen (HBsAg) as a VLP and immunogen, we hypothesize that it will serve as a suitable carrier molecule for the broadly neutralizing epitopes found in the membrane-proximal external region of the HIV-1 Env protein. In this Phase I SBIR proposal, we propose to create several variants of the HIV-derived epitope sequences fused to the HBsAg VLP moiety so that the most effective immunogens can be identified. The only way to evaluate the immunogenicity of a protein is by immunization, carried out initially in small animal models followed by clinical trials. The Specific Aims of the present Phase I proposal are as follows. - Specific Aim #1: Insert HIV-1 Env gp41 epitopes into the HBsAg. - Specific Aim #2: Evaluate secretion and antigenicity of chimeric HIV-HBsAg particles. - Specific Aim #3: Evaluate immunogenicity of chimeric HIV-HBsAg particles.