VLP-Based Antibody-Inducing Vaccines for HIV-1

描述(申请人提供)：艾滋病毒-1疫情在2007年造成约270万人新感染，总共约3300万艾滋病毒/艾滋病患者。临床试验表明，用病毒包膜蛋白的单体重组形式免疫不能预防HIV-1感染。然而，很明显，HIV-1Env含有能够诱导中和抗体的表位，而且这种抗体可以保护灵长类动物免受感染。 HIV-1env是一种跨膜糖蛋白。Env的外亚基(Gp120)和膜近端的外区(位于gp41亚基内)都含有抗原表位，这些表位是从感染患者中分离出的广谱中和单抗(MAbs)的靶标。已经投入了相当大的努力来创造可溶形式的环境三聚体。相对于单体gp120，这些分子在免疫原性方面的改善充其量是有限的。 创造改进的基于环境的免疫原的另一种方法是产生病毒样颗粒(VLP)。VLP是多价的，通常具有很强的免疫原性。HIV-1包膜蛋白全长存在于VLP表面，由Gag蛋白和细胞膜组成。这些VLP结构有可能代表环境三聚体尖峰的真实模拟。 要开发基于VLP的HIV-1疫苗，必须克服几个挑战。它们必须在高水平上生产。每个VLP上的Env分子的数量必须最大化。必须在不解离gp120亚基的情况下对gp160环境多肽进行加工，以产生功能形式的环境三聚体。可能还有必要将可变序列的免疫原性降至最低。 在创建携带HIV-1包膜蛋白的VLP的初步研究中，我们已经开始应对上述挑战。初步结果令人鼓舞，并为以VLP为基础的免疫原作为HIV-1疫苗候选进行更详细的工作奠定了基础。其目标是创造携带Env蛋白的VLP，其形式与目前病毒功能Env三聚体的愿景最相似。 第一阶段SBIR方案的具体目的如下：(1)制备用于生产VLP的优化的Env构建体；(2)制备具有不同Env序列的VLP构建体；以及(3)评估各种VLP诱导兔中和抗体的能力 如果基于VLP的环境免疫原被证明在诱导中和抗体方面优于可溶性gp120或gp140构建体，那么进一步的研究将形成第二阶段SBIR提案的基础。 与公共卫生有关：2007年，艾滋病毒/艾滋病疫情已导致200万人死亡和270万新感染者，总共有近3300万艾滋病毒/艾滋病患者。疫苗的开发被认为是减缓疫情所需的公共卫生措施的重要组成部分。这项研究计划旨在创造一种疫苗，可以诱导能够预防艾滋病毒感染的抗体。

DESCRIPTION (provided by applicant): The HIV-1 epidemic has resulted in ~2.7 million new infections in 2007 for a total of ~33 million people living with HIV/AIDS. Clinical trials have shown that HIV-1 infection cannot be prevented by immunization with monomeric recombinant forms of viral envelope (Env) proteins. However, it is clear that the HIV-1 Env contains epitopes that can induce neutralizing antibodies and that such antibodies can protect primates from infection. The HIV-1 Env is a transmembrane glycoprotein. Both the external subunit (gp120) and the membrane- proximal external region of Env (located within the gp41 subunit) contain epitopes that are the target of broadly neutralizing monoclonal antibodies (mAbs) isolated from infected patients. Considerable effort has been devoted to creating soluble forms of the Env trimer. The improvements in immunogenicity of these molecules relative to monomeric gp120 are limited at best. Another approach to creating improved Env-based immunogens is to produce virus-like particles (VLP). VLPs are multivalent and often very immunogenic. The full-length HIV-1 Env protein can be presented on the surface of VLPs composed of Gag protein and cellular membrane components. These VLP structures have the potential to represent true mimics of the Env trimer spike. Several challenges must be overcome to create HIV-1 vaccines based on VLPs. They must be produced at high levels. The number of Env molecules on each VLP must be maximized. Processing of the gp160 Env polypeptide must take place, without dissociation of the gp120 subunit, to create a functional form of the Env trimer. It might also be necessary to minimize the immunogenicity of the variable sequences. In preliminary studies on the creation of VLPs carrying HIV-1 Env proteins, we have begun to address the challenges outlined above. The preliminary results are encouraging and provide a basis for more detailed work on preparing VLP-based immunogens as candidates for HIV-1 vaccines. The objective is to create VLPs that carry the Env protein in a form that most resembles the current vision of the functional Env trimer of the virus. The Specific Aims of this Phase I SBIR proposal are as follows: (1) prepare optimized Env constructs for VLP production; (2) prepare VLP constructs with different Env sequences; and (3) evaluate the ability of various VLPs to induce neutralizing antibodies in rabbits If the VLP-based Env immunogens prove to be superior to soluble gp120 or gp140 constructs in their ability to induce neutralizing antibodies, then additional studies will form the basis of a Phase II SBIR proposal. PUBLIC HEALTH RELEVANCE: The HIV/AIDS epidemic has resulted in 2 million deaths and 2.7 million new infections in 2007, for a total of nearly 33 million people living with HIV/AIDS. Development of a vaccine is considered to be an essential component of the public health measures needed to slow the epidemic. This research proposal is designed to create a vaccine that can induce antibodies capable of preventing infection by the HIV virus.