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: 8410017
• 负责人: JULIE M. OVERBAUGH
• 金额: $ 67.75万
• 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 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8410017
• 关键词: Address; Affinity; Antibodies; Antibody Formation; Antibody Repertoire; 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; follow-up; insight; neutralizing antibody; novel; progenitor; research study; response; simian human immunodeficiency virus; superinfection

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. PUBLIC HEALTH RELEVANCE: It is thought that a protective vaccine response to HIV will require broad HIV-specific antibodies. We propose here to isolate and characterize such antibodies from naturally infected individuals. We will also study the process of evolution of such antibody responses, which is important for understanding how to elicit protective HIV antibodies.

描述(由申请人提供)：在猕猴模型中，HIV特异性中和抗体(NAB)已被证明可以预防SIV感染，这表明具有足够效力的NAB可以提供一些保护，防止人类感染HIV。鉴于全球流行的HIV毒株之间存在着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挑战病毒的效力，而且表现出跨亚型的广度和中和在高发地区传播的流通变种的能力。最近从艾滋病毒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能够诱导具有广泛特异性的NAB来应对HIV抗原，新的NAB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人身上分离出来的，是广泛的体细胞超突变的结果--这一过程是使用当前技术的疫苗免疫原不可能模仿的。因此，一个关键的问题是，不需要这种长期抗原刺激的广泛的NAB能否在感染的早期阶段被激发。我们已经确认了一名在感染HIV后6个月有明显交叉亚型广度的HIV特异性NAB反应的个体。我们还发现了由于双重感染而具有异常广泛和强大的精英中和活动的个体。我们假设，这些个体的NAB反应将不同于先前研究中检查的感染持续时间较长的单一感染个体，包括在体细胞超突变的程度上。在这里，我们建议对这些独特个体的NAB反应进行表征，这将包括定位NAB特异性以及克隆和表征相应的NAB。此外，我们将利用这些人在感染艾滋病毒和/或双重感染之前就可以获得的银行样本来检查艾滋病毒特异性NAB反应的演变--这在任何先前的研究中都是不可能的。我们还将继续筛查我们的队列中在感染早期就产生广泛NAB反应的个人。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。 与公共卫生相关：人们认为，对艾滋病毒的保护性疫苗反应将需要广泛的艾滋病毒特异性抗体。我们建议在这里从自然感染的个体中分离和鉴定这种抗体。我们也将研究这种进化的过程。 抗体反应，这对于了解如何诱导保护性艾滋病毒抗体很重要。