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

优化 HIV-1 gp120 V1/V2 结构域中的保护性疫苗靶标

• 批准号: 8410364
• 负责人: ABRAHAM PINTER
• 金额: $ 56.28万
• 依托单位: UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8410364
• 关键词: Affinity; Animals; Antibodies; Antibody Formation; Antigens; Binding; Cells; Chimeric Proteins; Cloning; Consensus Sequence; DNA; Drug Formulations; Epitopes; Genes; Goals; HIV; HIV Envelope Protein gp120; HIV vaccine; HIV-1; Heterogeneity; Immune; Immune response; Immunization; Immunoprecipitation; Infection; Integrins; Lead; Learning; Light; Macaca; Measures; Memory B-Lymphocyte; Methods; Modeling; Monoclonal Antibodies; Mutation; Oryctolagus cuniculus; Participant; Polysaccharides; Positioning Attribute; Property; Protein Glycosylation; Proteins; Protocols documentation; Relative (related person); Role; Screening procedure; Series; Serum; Site; Specificity; Structure; T-Lymphocyte; Testing; Thailand; Transfection; Vaccinated; Vaccination; Vaccines; Variant; Viral; Virus Diseases; base; design; expression vector; glycosylation; immunogenicity; in vivo; mutant; neutralizing antibody; neutralizing monoclonal antibodies; nonhuman primate; novel; programs; protein folding; receptor; research study; response; scaffold; simian human immunodeficiency virus; vaccine development; vector

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.

描述（由申请人提供）：最近的信息揭示了 HIV-1 V1/V2 结构域在病毒感染中的重要性以及作为保护性潜在靶标的重要性。 疫苗。 V1/V2 结构域已被证明是从 HIV 感染者中分离出的单克隆抗体 (mAb) 数量不断增加的关键决定因素，这些单克隆抗体针对四级中和表位并具有广泛且有效的中和活性。除了 V1/V2 区域作为经典中和靶点的作用之外，积累的其他证据表明，保守的 V2 序列与 4¿7-整联蛋白受体之间的相互作用会刺激肠道中一部分活化 T 细胞的感染，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 RV144 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 中和靶标具有高度构象和聚糖依赖性，并且由于蛋白质折叠和糖基化的变化，该区域的结构异质性使开发基于 V1/V2 的疫苗变得复杂。该项目的目的是全面表征 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 V1/V2 表位的特异性免疫原和疫苗策略，有效引发有助于预防感染的抗体。该项目开发的新型 V1/V2 免疫原的功效将首先由麻省大学的 Shan Lu 博士在兔子模型中进行评估，并在本研究结束时由 WNPRC 的 Shiu-Lok Hu 博士在非人类灵长类动物攻击模型中进行评估。这些研究产生的 V1/V2 域靶标的优化应该对设计更有效的 HIV 疫苗做出重要贡献。 公共卫生相关性：最近在泰国结束的 RV144 疫苗试验发现提供了部分保护（31%），因此在开发 HIV 保护性疫苗方面取得了一些进展。对 RV144 参与者免疫参数的分析意外发现，保护的唯一正相关是针对天然 V1/V2 结构域的抗体的存在，该抗体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点。我们提案的目标是在我们过去的研究的基础上，充分表征 V1/V2 结构域的结构和免疫学特性，以便优化该区域作为保护性疫苗的靶点。