Autologous HIV antibodies for viral control

用于病毒控制的自体 HIV 抗体

• 批准号: 10327100
• 负责人: Jonathan Li
• 金额: $ 28.65万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10327100
• 关键词: AIDS clinical trial group; Address; Aftercare; Antibody Formation; Antibody Response; Antiviral Agents; Antiviral Response; Autologous; Automobile Driving; B-Lymphocytes; Biological Assay; Chronic; Development; Disease remission; Early treatment; Goals; HIV; HIV Antibodies; HIV Infections; Immune response; Individual; Infection; Interruption; Knowledge; Lead; Mediating; Participant; Persons; Plasma; Play; Population; Proviruses; Research; Resistance; Role; Stochastic Processes; Thailand; Therapeutic Intervention; Time; Variant; Viral; Viral Antibodies; Virus; Virus Replication; Withholding Treatment; acute infection; adaptive immune response; antiretroviral therapy; antiviral immunity; chronic infection; cohort; experience; neutralizing antibody; preservation; pressure; response; viral rebound; virology

PROJECT SUMMARY The primary goals of the proposed study are to determine the impact of autologous neutralizing antibodies in selecting the rebounding HIV variants after treatment interruption and contributing to HIV post-treatment control. Although the majority of HIV-infected persons will experience rapid viral rebound after ART interruption, there are rare individuals, termed post-treatment controllers (PTCs), who demonstrate sustained virologic suppression for months or years after treatment cessation. Our analysis of the CHAMP study of HIV PTCs has shown an increase in post-treatment control for individuals initiating ART early after infection. However, key knowledge gaps in the field include our incomplete understanding of which viral variants will lead to HIV rebound after treatment interruption (i.e., the “reboundable reservoir”) and mechanisms behind post- treatment control, including how early ART initiation lowers the barrier to HIV remission. Neutralizing antibodies represent a key adaptive immune response against a broad range of viruses. While anti-HIV antibodies arise during untreated acute infection, maturation of the immune response requires time, as it can take several months before potent autologous neutralizing antibodies (aNAbs) against HIV are developed. However, continuous viral replication in the absence of ART allows for rapid viral escape and renders the humoral response largely ineffective in controlling HIV infection. Early ART initiation has been found to restrict the size and diversity of the HIV reservoir, while preserving B-cell antiviral immunity. In this proposal, we plan to assess the role of aNAbs in selecting for rebounding viral variants and mediating post-treatment HIV control. The proposed studies have the potential to lead to key paradigm shifts in the field, including that anti-HIV immune responses can mature and evolve after early ART initiation, that the viral populations driving HIV rebound during ART interruption is not a purely stochastic process, and provide the first mechanistic explanation behind the ability of early-ART initiation to lower the barrier to HIV remission.

项目摘要 这项研究的主要目的是确定自体中和抗体对 选择治疗中断后反弹的HIV变异体，并有助于HIV治疗后 控制虽然大多数艾滋病毒感染者在接受抗逆转录病毒治疗后会出现病毒迅速反弹， 中断，有罕见的个人，称为治疗后控制器（PTC），谁表现出持续的 治疗停止后数月或数年的病毒学抑制。我们对HIV的CHAMP研究的分析 PTC已经显示出在感染后早期开始ART的个体的治疗后控制增加。 然而，该领域的关键知识差距包括我们对哪些病毒变异将导致 治疗中断后HIV反弹（即，“反弹水库”）和机制背后的后， 治疗控制，包括早期抗逆转录病毒治疗如何降低艾滋病毒缓解的障碍。中和抗体 代表了针对广泛病毒的关键适应性免疫应答。当抗艾滋病毒抗体出现时， 在未经治疗的急性感染期间，免疫应答的成熟需要时间，因为它可能需要几个小时。 在开发出针对HIV的有效自体中和抗体（aNAb）之前的几个月。然而，在这方面， 在没有ART的情况下，连续的病毒复制允许快速的病毒逃逸，并使体液免疫系统 在控制艾滋病毒感染方面，应对措施基本无效。早期抗逆转录病毒治疗的启动已被发现限制大小 和多样性，同时保留B细胞抗病毒免疫力。在这份提案中，我们计划评估 aNAb在选择反弹病毒变体和介导治疗后HIV控制中的作用。的 拟议的研究有可能导致该领域的关键范式转变，包括抗艾滋病毒免疫 在早期ART启动后，反应可以成熟和发展， 在ART中断不是一个纯粹的随机过程，并提供背后的第一个机械解释 早期抗逆转录病毒疗法启动降低艾滋病毒缓解障碍的能力。