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，以及作为潜在的保护目标 疫苗。V1/V2结构域已被证明是从HIV感染者中分离出的越来越多的单抗的关键决定因素，这些单抗以四元中和表位为靶标，具有广泛而有效的中和活性。除了V1/V2区作为经典中和靶点的作用外，其他证据表明，保守的V2序列与整合素受体之间的相互作用可刺激肠道中一部分激活的T细胞的感染，这可能对体内感染起重要作用，这种相互作用可被抗V2单抗抑制。最后，最近在泰国进行的RV144疫苗试验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中和靶点既是高度构象的，也是糖依赖的，而基于V1/V2的疫苗的开发因该区域的结构异质性而变得复杂，这是由于蛋白质折叠和糖基化的变化。本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，识别和表征该区域的保护性表位，并开发针对保守的V1/V2表位的免疫原和疫苗策略，以有效地诱导抗体，从而有助于预防感染。由该计划开发的新型V1/V2免疫原的有效性将首先由加州大学马萨诸塞州分校的陆山博士在兔子模型中进行评估，并在本研究接近尾声时由WNPRC的胡绍乐博士在非人类灵长类动物挑战模型中进行评估。这些研究产生的V1/V2领域靶标的优化应该是对设计更有效的艾滋病毒疫苗的重要贡献。

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.