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）已在猕猴模型中显示出对SHIV感染的保护作用，这表明足够效力的nab可以对人类HIV感染提供一定的保护。鉴于全球流行的艾滋病毒毒株具有相当大的遗传和抗原多样性，关键是保护性Nab反应不仅表现出对一种特定挑战病毒的效力，而且还表现出跨亚型广度和中和在高发地区传播的流行变异的能力。最近从艾滋病毒感染者中分离出了几种具有这些特征的nab。这些令人兴奋的发现表明，人类免疫系统有能力对HIV抗原产生具有广泛特异性的抗体，新的抗体已经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，是广泛的体细胞超突变的结果——这一过程是不可能用现有技术的疫苗免疫原模拟的。因此，一个关键的问题是，不需要长期抗原刺激的广泛nab能否在感染的早期阶段被诱导出来。我们已经确定了一个在HIV感染后6个月具有显著跨亚型广度的HIV特异性Nab反应的个体。我们还确定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次感染个体，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，包括绘制Nab特异性，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/或重复感染之前的可用样本来检查HIV特异性Nab反应的演变，这在以往的任何研究中都是不可能的。我们还将继续筛选在感染早期就出现广泛Nab反应的个体。这些研究旨在揭示开发广泛和有效的hiv特异性nab的新途径。

项目成果

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

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