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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.