Fcgamma receptor-mediated suppression of immunodeficiency virus replication

 描述（由申请人提供）：在过去几年中，从HIV-1感染者中分离出了新一代特别有效的广泛中和抗体（bNAb）。被动转移实验表明，这些抗体中的一些能够在动物中抑制病毒复制低于检测限，这重新引起了人们对开发基于抗体的治疗HIV-1感染的疗法的兴趣。越来越多的证据还表明，抗体的Fc受体（FcR）依赖性功能，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，以及抗体调理的免疫复合物的吞噬作用，对于保护免受免疫缺陷病毒感染很重要。这些进展提出了一种可能性，即可以开发旨在最大化FcR介导的抗体功能的免疫疗法，以在没有连续抗逆转录病毒治疗的情况下耗尽病毒库并遏制HIV-1复制。使用对HIV-1感染的细胞具有强效ADCC活性的bNAb变体，并以致病性CCR 5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FcRs介导的抗体抑制免疫缺陷病毒复制的基本抗病毒机制。在目的1中，我们将确定种属特异性差异和多态性如何影响恒河猴中抗体的FcR识别，从而为在这种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的变体与修饰以增强FcR依赖性功能，以确定其清除动物中病毒感染细胞的能力。对于这些研究，将使用仅限于单周期感染的病毒，以将抗体对病毒感染细胞的FcR介导效应与其对病毒中和的效应分离。在目标3中，我们将比较被动转移的抗体，有和没有修饰，以增强FcR相互作用的能力，消耗病毒水库和延迟病毒反弹的SHIV感染的动物后，撤回抗逆转录病毒治疗。在目标4中，我们将这些研究扩展到使用AAV载体进行持续的抗体递送，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SHIV复制。这些前所未有的研究将推进我们对抗体的非中和功能的能力的基本理解，以包含免疫缺陷病毒感染和增强FcR介导的抗病毒活性在HIV-1感染的抗体治疗的临床前模型的治疗影响。

 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.