Optimizing protective vaccine targets in the V1/V2 domain of HIV-1 gp120

描述（由申请人提供）：最近的信息揭示了HIV-1的V1/V2结构域在病毒感染中的重要性，并作为保护性治疗的潜在靶点。 疫苗。V1/V2结构域已被证明是越来越多的从HIV感染的受试者中分离的单克隆抗体（mAb）的关键决定因素，所述单克隆抗体（mAb）靶向第四中和表位并具有广泛且有效的中和活性。除了V1/V2区作为经典中和靶点的作用外，其他证据也已积累，表明保守的V2序列和4、7-整联蛋白受体之间的相互作用刺激肠道中活化T细胞的一部分的感染，这可能对体内感染很重要，并且这种相互作用被抗V2 mAb抑制。最后，最近在泰国进行的RV 144疫苗试验中的免疫参数分析表明，与我们开发的V1/V2融合蛋白结合的抗体与保护作用独特相关。我们实验室和其他实验室的研究表明，有效的V1/V2中和靶点具有高度的构象和聚糖依赖性，由于蛋白质折叠和糖基化的变化，开发基于V1/V2的疫苗因该区域的结构异质性而变得复杂。该项目的目的是充分表征V1/V2结构域的结构、功能和免疫学特性，鉴定和表征该区域的保护性表位，并开发针对保守V1/V2表位的免疫原和疫苗策略，这些表位有效地引发有助于保护免受感染的抗体。由该项目开发的新型V1/V2免疫原的有效性最初将由麻省大学的Shan Lu博士在兔模型中进行评价，并在本研究结束时由WNPRC的Shiu-Lok Hu博士在非人灵长类动物攻毒模型中进行评价。从这些研究中产生的V1/V2结构域中的靶点的优化应该是对设计更有效的HIV疫苗的重要贡献。 公共卫生相关性：最近在泰国结束的RV 144疫苗试验提供了部分保护（31%），这一发现使开发艾滋病毒保护性疫苗的工作取得了一些进展。对RV 144参与者的免疫参数的分析意外地发现，保护的唯一正相关是存在针对天然V1/V2结构域的抗体，其表达为我们提供的融合蛋白，这表明V1/V2结构域是关键的疫苗靶标。我们建议的目标是建立在我们过去的研究，以充分表征V1/V2结构域的结构和免疫学特性，以优化该区域作为保护性疫苗的靶点。

DESCRIPTION (provided by applicant): Recent information has shed new light on the importance of the V1/V2 domain of HIV-1 in viral infection and as a potential target for protective vaccines. The V1/V2 domain has been shown to be a critical determinant of an increasing number of monoclonal antibodies (mAbs) isolated from HIV-infected subjects that that target quaternary neutralization epitopes and possess broad and potently neutralizing activities. In addition to the role of the V1/V2 region as a classical neutralization target other evidence has accumulated showing that the interaction between a conserved V2 sequence and the ¿4¿7-integrin receptor stimulates infection of a fraction of activated T cells in the gut that may be important for infection in vivo, and that this interaction is inhibited by anti-V2 mAbs. Finally, a analysis of immune parameters in the RV144 vaccine trial recently carried out in Thailand showed that antibodies that bind to a V1/V2 fusion protein that we developed uniquely correlated with protection. Studies from our lab and others have shown that potent V1/V2 neutralization targets are both highly conformational and glycan-dependent, and developing V1/V2-based vaccines is complicated by the structural heterogeneity of this region, due to variation in both protein folding and glycosylation. The aims of this project are to fully characterize the structural, functional and immunological properties of the V1/V2 domain, to identify and characterize protective epitopes in this region and to develop immunogens and vaccine strategies specific for conserved V1/V2 epitopes that efficiently elicit antibodies that contribute to protection against infection. The efficacy of novel V1/V2 immunogens developed by this program will be evaluated initially in a rabbit model by Dr. Shan Lu at UMass and towards the end of this study in a non-human primate challenge model by Dr. Shiu-Lok Hu at the WNPRC. The optimization of targets in the V1/V2 domain arising from these studies should be an important contribution towards the design of more effective HIV vaccines. PUBLIC HEALTH RELEVANCE: Some progress towards developing a protective vaccine for HIV was made by the finding that the RV144 vaccine trial recently concluded in Thailand provided partial protection (31%). An analysis of immune parameters in the RV144 participants made the unexpected discovery that the only positive correlate of protection was the presence of antibodies against the native V1/V2 domain, expressed as a fusion protein that we provided, suggesting that the V1/V2 domain is a critical vaccine target. The goals of our proposal are to build on our past studies to fully characterize the structure and immunological properties of the V1/V2 domain, in order to optimize this region as a target for a protective vaccine.