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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(申请人提供)：在过去的几年里，从HIV-1感染者身上分离出了新一代特别有效的广谱中和抗体(BNAbs)。被动转移实验表明，其中一些抗体能够在动物体内将病毒复制抑制在检测到的限度以下，这重新引起了人们对开发基于抗体的治疗HIV-1感染的兴趣。越来越多的证据也表明，抗体的Fc受体(FCR)依赖功能，如通过抗体依赖的细胞介导的细胞毒作用(ADCC)消除病毒感染的细胞和吞噬抗体调理的免疫复合体，对于预防免疫缺陷病毒感染是重要的。这些进展提出了一种可能性，即在没有持续抗逆转录病毒治疗的情况下，旨在最大限度地发挥FCR介导的抗体功能的免疫疗法可能会开发出耗尽病毒库并遏制HIV-1复制的免疫疗法。使用对HIV-1感染细胞具有强大ADCC活性的bNAb的变体，以及感染致病的CCR5嗜性SIV的恒河猴作为动物模型，我们将特别讨论这一假说，以及FCR介导的抗体对抑制免疫缺陷病毒复制至关重要的基本抗病毒机制。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抗体的FCR识别，为在这个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的变体和修改，以增强FCR依赖的功能，以了解它们清除动物体内受病毒感染的细胞的能力。在这些研究中，将使用仅限于单个感染周期的病毒，将FCR介导的抗体对病毒感染细胞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的抗体和没有修饰的抗体，以增强FCR相互作用，从而在停止抗逆转录病毒治疗后耗尽SHV感染动物的病毒库和延迟病毒反弹的能力。在目标4中，我们将把这些研究扩展到使用AAV载体进行持续抗体传递，以确定在停止抗逆转录病毒治疗后，增强的FCR介导的抗病毒活性是否可以持久地抑制SIV的复制。这些史无前例的研究将促进我们对抗体的非中和功能抑制免疫缺陷病毒感染的能力以及在HIV-1感染的抗体治疗的临床前模型中增强FCR介导的抗病毒活性的治疗效果的基本理解。