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）：已证明HIV特异性中和抗体（NABS）可以预防猕猴模型中的SHIV感染，这表明足够的效力可以提供对人类HIV感染的一些保护。鉴于全球循环艾滋病菌株之间相当大的遗传和抗原多样性，批评性的NAB反应不仅表现出一种特定挑战病毒的效力，而且还表现出跨补充宽度的效力，而且还表现出跨性别的宽度和中和循环变体的能力区域。最近已经从HIV感染的个体中分离出具有这些特征的几种NAB。这些令人兴奋的发现证明了人类免疫系统在响应艾滋病毒抗原方面引起具有广泛特异性的NAB的能力，并且已经利用了新的NAB来研究被动免疫保护。但是，这些广泛的抗体是从被感染了多年的个体中分离出来的，是广泛的体细胞超突变的结果 - 这种过程无法使用当前技术模仿疫苗免疫原。因此，一个关键的问题是，不需要这种长期抗原刺激的广泛NAB是否可以在感染的早期阶段引起。我们已经确定了一个患有HIV特异性NAB反应的人，在HIV感染后6个月时，具有明显的跨额外宽度。我们还确定了由于超感染而具有异常广泛和有效的精英中和活性的个体。我们假设这些个体中的NAB反应与在先前研究中检查的单个感染持续时间的单独感染的个体不同，包括在体细胞超成名的程度上。在这里，我们建议在这些独特的个体中表征NAB响应，其中包括映射NAB特异性和克隆并表征相应的NAB。此外，我们将利用这些人在艾滋病毒感染和/或超级感染之前从这些人那里获得的库存样本，以检查HIV特异性NAB反应的演变 - 这种方法在任何先前的研究中都无法使用。我们还将继续为在感染早期发展较广泛反应的个人筛选我们的队列。这些研究旨在发现开发广泛和有效的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