Bioinformatics and Statistics

生物信息学和统计学

• 批准号: 10631876
• 负责人: Kshitij Wagh
• 金额: $ 34.61万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-07 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10631876
• 关键词: Acceleration; Affinity; Antibodies; Antibody Response; Antigens; B cell repertoire; B-Lymphocytes; Bioinformatics; Biological; Biological Models; Biological Phenomena; Biology; Chronic; Collaborations; Complement; Complex; Data; Development; Epitopes; Evolution; Foundations; Glycoproteins; Goals; HIV Infections; HIV-1; Helper-Inducer T-Lymphocyte; Human; Immunogenetics; Immunoglobulin Somatic Hypermutation; Individual; Infection; Macaca mulatta; Modeling; Molecular; Pathway Analysis; Pathway interactions; Pattern; Polysaccharides; Prevalence; Publishing; Reproducibility; Resistance; Rhesus; Series; Statistical Models; Structure of germinal center of lymph node; System; T-Lymphocyte; Testing; Translating; Vaccinated; Vaccination; Vaccine Design; Vaccines; Variant; Viral; computational pipelines; design; in vivo; in vivo Model; iterative design; longitudinal analysis; neutralizing antibody; novel; pressure; prevent; protective efficacy; simian human immunodeficiency virus; statistics; transcriptomics; vaccine efficacy; vaccine evaluation

PROJECT SUMMARY Vaccines that can induce broadly neutralizing antibodies (bNAbs) will be needed to protect against the global diversity of HIV-1 strains, however they do not currently exist (1,2). Vaccine induction of bNAbs will require two critical steps. First, priming of the appropriate bNAb precursors that, due to unusual features, are rare in the naïve human B-cell repertoire (3–5). Second, such precursors will need to be guided to acquire critical somatic hypermutations that confer heterologous neutralization potency and breadth (6). While it is clear that bNAbs evolve in natural HIV-1 infections through years of Env-antibody (Ab) coevolution, it is not clear how to trans- late these findings to design immunogens that can reproducibly prime and mature bNAbs across multiple hosts (1,5,7). In our last HIVRAD project, we developed a novel rhesus macaque (RM) SHIV infection model that re- capitulated several key features of Env-bNAb coevolution (8,9). We also showed that prior vaccination and in- fection with SHIVs bearing particular germline-targeting Envs could accelerate bNAb development. Thus, our rhesus model system thus provides a unique setting where reproducible induction of bNAbs in (S)HIV infec- tions can be studied. In this renewal, we will leverage this system to develop a vaccination and SHIV infection strategy that will lead to development of V3 glycan bNAbs in an accelerated and reproducible manner across multiple rhesus hosts. Our scientific premise is that a better understanding of the common Env-Ab coevolu- tionary patterns leading to V3 glycan bNAb development will allow design of immunogens that can prime and mature multiple V3 glycan bNAb lineages. Our Bioinformatics and Statistics Core (Core C) will provide bioin- formatic and statistical modeling analyses to facilitate these overall HIVRAD goals. We will analyze Env evolu- tion in SHIV-infected RMs from Project 1 by applying our novel computational pipeline to longitudinal se- quence data generated by Core B. We will identify the similarities and differences between the neutralization profiles of newly identified rhesus V3 glycan bNAbs (Project 1) and previously known V3 glycan bNAbs (Aim 2). Using the above two studies, we will iteratively design immunogens that are capable of engaging precur- sors of multiple V3 glycan bNAb lineages and of maturing them towards neutralization breadth in collaboration with Core B and Project 3 (Aim 3). Finally, we will provide statistical modeling of in vivo vaccine efficacy (Pro- ject 1) and other complex biological problems across all Projects.

项目总结 需要能够诱导广谱中和抗体(BNAbs)的疫苗来预防全球 艾滋病毒-1毒株的多样性，但它们目前还不存在(1，2)。BNAbs的疫苗诱导将需要两个 关键步骤。首先，适当的bNAb前体的启动，由于不寻常的特征，在 幼稚的人类B细胞谱系(3-5)。其次，需要引导这样的前体获得关键的体细胞 赋予异源中和效力和广度的超突变(6)。虽然很明显，bNAbs 通过多年的环境抗体(Ab)共同进化在自然感染的HIV-1中进化，目前尚不清楚如何反式- 晚些时候，这些发现设计了可以在多个宿主上重复启动和成熟的bNAbs的免疫原 (1，5，7)。在我们的上一个HIVRAD项目中，我们开发了一种新的恒河猴(RM)SHV感染模型，该模型可以重新 放弃了Env-bNAb共同进化的几个关键特征(8，9)。我们还表明，之前接种疫苗和在- 用带有特定生殖系靶向环境的SHIV感染可以加速bNAb的发育。因此，我们的 因此，恒河猴模型系统提供了一种独特的环境，在这种环境中，可重复诱导的bNAbs在(S)艾滋病毒中感染- 我们可以研究这些问题。在这次更新中，我们将利用这一系统来开发疫苗接种和SHV感染 战略将导致以加速和可重复的方式开发V3糖蛋白bNAbs 多个恒河猴宿主。我们的科学前提是，更好地理解共同的Env-Ab协同进化- 导致V3糖蛋白bNAb发展的字典模式将允许设计能够启动和 成熟的多个V3糖蛋白bNAb谱系。我们的生物信息学和统计核心(核心C)将提供生物信息学- 形式化和统计建模分析，以促进HIVRAD的这些总体目标。我们将分析环境演变- 将我们的新型计算流水线应用到纵向Se-Se中，从而在项目1中感染了SHIV的RMS中进行了检测。 由核心B生成的序列数据。我们将确定中和和 新发现的恒河猴V3糖链bNAbs(项目1)和已知的V3糖链bNAbs(AIM 2)。利用上述两项研究，我们将反复设计能够与疾病发生相关的免疫原。 多个V3糖蛋白bNAb谱系的SOR以及它们在协作中走向成熟的中和广度 核心B和项目3(目标3)。最后，我们将提供体内疫苗效力的统计建模(Pro- 目标1)和所有项目中的其他复杂的生物问题。