CHARACTERIZATION OF HIV-1 ANTIBODY RESPONSES IN CHRONICALLY INFECTED WOMEN

慢性感染女性 HIV-1 抗体反应的特征

• 批准号: 8889191
• 负责人: JULIE M. OVERBAUGH
• 金额: $ 67.38万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-02 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8889191
• 关键词: Address; Affinity; Antibodies; Antibody Repertoire; Antibody Response; Antigenic Diversity; Antigens; Area; Characteristics; Cloning; Epitopes; Evolution; Exhibits; Exposure to; Genes; Genetic Variation; HIV; HIV Antibodies; HIV Antigens; HIV Infections; HIV vaccine; HIV-1; High Risk Woman; Human; Immune; Immune system; Immunoglobulin Somatic Hypermutation; Incidence; Individual; Infection; Light; Lymphocyte; Macaca; Maps; Methods; Modeling; Monoclonal Antibodies; Mutation; Pathway interactions; Polysaccharides; Population; Process; Property; Receptors, Antigen, B-Cell; Research; Research Design; Sampling; Specificity; Staging; Technology; Time; Vaccines; Variant; Virus; Woman; cohort; deep sequencing; follow-up; insight; neutralizing antibody; novel; progenitor; research study; response; simian human immunodeficiency virus; superinfection; vaccine response

DESCRIPTION (provided by applicant): HIV-specific neutralizing antibodies (Nabs) have been shown to protect against SHIV infection in the macaque model, suggesting that Nabs of sufficient potency could provide some protection against HIV infection in humans. Given the considerable genetic and antigenic diversity among global circulating strains of HIV, it is critica that protective Nab responses exhibit not only potency for one particular challenge virus, but also cross-subtype breadth and the capacity to neutralize circulating variants that are spreading in high incidence areas. Several Nabs with these characteristics have recently been isolated from HIV-infected individuals. These exciting discoveries demonstrate the capacity of the human immune system to elicit Nabs with broad specificity in response to HIV antigens, and the new Nabs are already being exploited to study passive immune protection. However, these broad antibodies, which were isolated from individuals who had been infected for many years, are the result of extensive somatic hypermutation -- a process that is not possible to mimic with a vaccine immunogen using current technologies. Thus, a critical question is whether broad Nabs that do not require such long-term antigenic stimulation can be elicited at earlier stages in infection. We have identified an individual who has a HIV-specific Nab response with significant cross-subtype breadth at 6 months after HIV infection. We have also identified individuals with exceptionally broad and potent elite neutralizing activity as a result of superinfection. We hypothesize that the Nab responses in these individuals will be distinct from those of singly-infected individuals with longer duration of infection examined in prior studies, including in the extent of somatic hypermutation. Here we propose to characterize the Nab responses in these unique individuals, which will include mapping the NAb specificity and cloning and characterizing the corresponding Nabs. In addition, we will take advantage of banked samples available from these individuals starting before their HIV infection and/or superinfection to examine the evolution of the HIV-specific Nab response -- an approach that has not been possible in any prior studies. We will also continue to screen our cohort for individuals who develop broad Nab responses very early in their infection. These studies are designed to uncover novel pathways to developing broad and potent HIV-specific Nabs.

描述（由申请人提供）：HIV 特异性中和抗体（Nab）已被证明可以在猕猴模型中防止 SHIV 感染，这表明具有足够效力的 Nab 可以为人类提供一定程度的针对 HIV 感染的保护。鉴于全球流行的HIV病毒株之间存在相当大的遗传和抗原多样性，至关重要的是，保护性Nab反应不仅表现出对一种特定攻击病毒的效力，而且还表现出跨亚型的广度和中和在高发地区传播的流行变异的能力。最近从 HIV 感染者身上分离出了几种具有这些特征的 Nab。这些令人兴奋的发现证明了人类免疫系统有能力引发对 HIV 抗原具有广泛特异性的 Nab，并且新的 Nab 已被用于研究被动免疫保护。然而，这些广泛的抗体是从感染多年的个体中分离出来的，是广泛体细胞超突变的结果——使用现有技术的疫苗免疫原不可能模拟这一过程。因此，一个关键问题是是否可以在感染的早期阶段引发不需要这种长期抗原刺激的广泛 Nab。我们已经确定了一个人在感染 HIV 后 6 个月时出现了 HIV 特异性 Nab 反应，并且具有显着的跨亚型广度。我们还发现了由于重复感染而具有异常广泛和有效的精英中和活性的个体。我们假设这些个体的 Nab 反应将不同于先前研究中检测的感染持续时间较长的单一感染个体的反应，包括体细胞超突变的程度。在这里，我们建议表征这些独特个体的 Nab 反应，其中包括绘制 NAb 特异性以及克隆和表征相应的 Nab。此外，我们将利用这些个体在 HIV 感染和/或重复感染之前获得的储存样本来检查 HIV 特异性 Nab 反应的演变，这是之前任何研究中不可能实现的方法。我们还将继续在我们的队列中筛选在感染早期就产生广泛 Nab 反应的个体。这些研究旨在揭示开发广泛且有效的 HIV 特异性抗体的新途径。

项目成果

Quantifying evolutionary constraints on B-cell affinity maturation.

• DOI: 10.1098/rstb.2014.0244
• 发表时间: 2015-09-05
• 期刊: Philosophical transactions of the Royal Society of London. Series B, Biological sciences
• 作者: McCoy CO;Bedford T;Minin VN;Bradley P;Robins H;Matsen FA 4th
• 通讯作者: Matsen FA 4th

Likelihood-Based Inference of B Cell Clonal Families.

• DOI: 10.1371/journal.pcbi.1005086
• 发表时间: 2016-10
• 期刊: PLoS computational biology
• 影响因子: 4.3
• 作者: Ralph DK;Matsen FA 4th
• 通讯作者: Matsen FA 4th