Fcgamma receptor-mediated suppression of immunodeficiency virus replication

Fcγ受体介导的免疫缺陷病毒复制抑制

基本信息

批准号：
9275920
负责人：
David T Evans
金额：
$ 76.52万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-15 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9275920
关键词：
Address Affect Affinity Animal Model Animals Antibodies Antigen-Antibody Complex Antiviral Agents CCR5 gene Cells Dependovirus Detection Development Engineering Fc Receptor Fc domain Foundations Generations Genetic Polymorphism HIV-1 Human IgG1 IgG2 IgG3 IgG4 Immune system Immunoglobulin G Immunologic Deficiency Syndromes Immunotherapy Individual Infection Macaca Macaca mulatta Mediating Modeling Modification Molecular Cloning Monoclonal Antibodies Muscle Cells Orthologous Gene Passive Transfer of Immunity Pathogenicity Phagocytosis Plasma Pre-Clinical Model Primates Specificity Testing Therapeutic Variant Viral reservoir Virus Virus Diseases Virus Replication Withdrawal adeno-associated viral vector antibody-dependent cell cytotoxicity antiretroviral therapy base design experimental study flexibility in vivo interest mutant neutralizing antibody prevent public health relevance receptor receptor binding simian human immunodeficiency virus viral RNA viral rebound

项目摘要

DESCRIPTION (provided by applicant): Over the past few years, a new generation of particularly potent broadly neutralizing antibodies (bNAbs) have been isolated from HIV-1-infected individuals. Passive transfer experiments showing that some of these antibodies are able to suppress virus replication below the limit of detection in animals have renewed interest in the development of antibody-based therapies to treat HIV-1 infection. Increasing evidence also suggests that Fc¿ receptor (FcR)-dependent functions of antibodies, such as the elimination of virus-infected cells by antibody-dependent cell-mediated cytotoxicity (ADCC) and the phagocytosis of antibody-opsonized immune complexes, are important for protection against immunodeficiency virus infection. These advances raise the possibility that immunotherapies designed to maximize FcR-mediated functions of antibodies may be developed to deplete viral reservoirs and contain HIV-1 replication in the absence of continuous antiretroviral therapy. Using variants of a bNAb with potent ADCC activity against HIV-1-infected cells, and infection of rhesus macaques with a pathogenic CCR5-tropic SHIV as an animal model, we will specifically address this hypothesis, as well as the fundamental antiviral mechanisms of antibodies mediated by FcRs important for suppressing immunodeficiency virus replication. In Aim 1, we will determine how species-specific differences and polymorphisms affect FcR recognition of antibodies in the rhesus macaque to provide the foundation necessary for investigating FcR-mediated antiviral activities of antibodies in this primate model. In Aim 2, we will compare variants of a bNAb with modifications to enhance FcR-dependent functions for their ability to clear virus-infected cells in animals. For these studies, will use viruses that are limited to a single cycle of infection to uncouple the FcR-mediated effects of antibodies on virus-infected cells from their effects on virus neutralization. In Aim 3, we will compare passively transferred antibodies with and without modifications to enhance FcR interactions for the ability to deplete viral reservoirs and delay viral rebound in SHIV-infected animals after withdrawal of antiretroviral therapy. In Aim 4, we will extend these studies to the use of AAV vectors for sustained antibody delivery to determine if enhanced FcR-mediated antiviral activity can durably suppress SHIV replication after discontinuing antiretroviral therapy. These unprecedented studies will advance our basic understanding of the capacity of non-neutralizing functions of antibodies to contain immunodeficiency virus infection and the therapeutic impact of enhancing FcR-mediated antiviral activity in a pre-clinical model of antibody treatment for HIV-1 infection.

描述（由申请人提供）：在过去的几年中，从 HIV-1 感染个体中分离出新一代特别有效的广泛中和抗体（bNAb），表明其中一些抗体能够抑制病毒。动物体内的复制低于检测限，这重新引起了人们对开发基于抗体的疗法来治疗 HIV-1 感染的兴趣。抗体的受体（FcR）依赖性功能，例如通过抗体依赖性细胞介导的细胞毒性（ADCC）消除病毒感染的细胞以及抗体调理免疫复合物的吞噬作用，对于预防免疫缺陷病毒感染的进展非常重要。在缺乏持续抗逆转录病毒治疗的情况下，可能会开发出旨在最大限度地发挥 FcR 介导的抗体功能的免疫疗法来耗尽病毒库并抑制 HIV-1 复制。由于 bNAb 的变体对 HIV-1 感染的细胞具有有效的 ADCC 活性，并且以致病性 CCR5 嗜性 SHIV 感染恒河猴作为动物模型，我们将专门讨论这一假设，以及抗体介导的基本抗病毒机制FcR 对抑制免疫缺陷病毒复制很重要在目标 1 中，我们将确定物种特异性差异和多态性如何影响恒河猴中 FcR 识别抗体。为在该灵长类动物模型中研究 FcR 介导的抗体抗病毒活性提供必要的基础。在目标 2 中，我们将比较 bNAb 的变体，以增强 FcR 依赖性功能，以增强其清除动物中病毒感染细胞的能力。研究将使用仅限于单个感染周期的病毒来将抗体对病毒感染细胞的 FcR 介导的影响与其对病毒中和的影响分开。在目标 3 中，我们将比较被动转移。在目标 4 中，我们将这些研究扩展到使用 AAV 载体进行持续抗体递送。以确定增强的 FcR 介导的抗病毒活性是否可以在停止抗逆转录病毒治疗后持久抑制 SHIV 复制，这些前所未有的研究将增进我们对非中和能力的基本了解。抗体遏制免疫缺陷病毒感染的功能以及在 HIV-1 感染抗体治疗临床前模型中增强 FcR 介导的抗病毒活性的治疗影响。