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Exploring antibody-Fc effector function in humanized mouse models of HIV latency

探索 HIV 潜伏期人源化小鼠模型中的抗体 Fc 效应子功能

基本信息

批准号：
9050087
负责人：
Priti Kumar
金额：
$ 22.09万
依托单位：
YALE UNIVERSITY
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：
2015-12-01 至 2017-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9050087
关键词：
Animal Model Anti-Retroviral Agents Antibodies Binding Biological Assay CCR5 gene CD4 Positive T Lymphocytes Capsid Carrying Capacities Cell Count Cells Code Collaborations Complement Coupled DNA Dinitrophenols Disease Disease remission Dose Elements Epitopes Frequencies Generations Genomic DNA Glycoproteins Grant HIV HIV Infections Human Immune Individual Injection of therapeutic agent Intramuscular Investigation Knowledge Leukocytes Life Light Measurement Medicine Modeling Monitor Mouse Strains Mus Muscle Natural Killer Cells Patients Peripheral Persons Pharmaceutical Preparations Phase Plasma Population Prevention Production Proviruses Recombinants Recruitment Activity Role Serotyping Skeletal Muscle Surface System T memory cell Testing Tetanus Helper Peptide Tetracyclines Therapeutic Therapeutic Effect Time Treatment Efficacy Viral Viral Load result Viral reservoir Viremia antiretroviral therapy base college complement system expectation gp160 gutless adenoviral vector humanized mouse interest man mouse model neutralizing antibody nonhuman primate novel novel strategies peptidomimetics peripheral blood prevent promoter prophylactic public health relevance simian human immunodeficiency virus small molecule success transgene expression

项目摘要

DESCRIPTION (provided by applicant): There is currently considerable emphasis on strategies for eradicating HIV from infected individuals. Although much effort is focused on reactivating integrated provirus using small molecules, a second possibility is using broadly neutralizing antibodies (bNAbs) that are highly potent and active against diverse strains and clades of HIV. Recent evidence demonstrating the ability of bNAbs in delaying viral rebound after stopping antiretroviral treatment (ART) indicate that these antibodies may be able to clear or remove cells expressing envelope glycoprotein on their surface, effectively reducing the pool size of persistently-infected cells. We propose to investigate a role for bNAbs in actively eliminating or reducing the size of the persistent viral reservoir, in novel humanized models of ART-suppressed HIV infection that support antibody-effector function. In the first of three specific aims, we will construct `gutted' or helper-dependent adenoviral (HDAd) vectors, encoding the heavy and light chains of three second-generation bNAbs, in view of the downstream intramuscular application in animal models described in Aims 2 and 3. In the second aim, these vectored bNABs will be tested in HIV-infected humanized BLT mice, in which viral loads will be suppressed to undetectable levels by ART, for measurements of the latent viral pool size by genomic DNA qPCR and viral outgrowth assays. In particular, novel humanized mouse models that have active complement and functional natural killer cells will be used to assess the role of bNAb effector function in shrinking the persistently infected reservoir. In the final aim, the vectored bNAbs will be tested for their ability to shrink viral reservoirs in humanized mice derived using peripheral blood leukocytes from ART-suppressed HIV+ patients with undetectable plasma viral loads. On the basis of the investigations to be conducted in the R21 phase of this application, we anticipate establishing a critical role for bNAb-effector activit targeting persistent viral reservoirs. The R33 phase of the application will extend these studies to the testing of tetracycline-regulable bnAbs encoded in HDAds, possible due to large carrying capacity of HdAds (~30 kb). In addition to exploring newer, more potent bNAbs, we will also test the use of the recently described eCD4-Ig, that encodes both soluble CD4-Ig and a CCR5 peptidomimetic and ARM-Hs, which are bivalent small molecules capable of binding the CD4 binding pocket of gp160 and also recruiting anti-dinitrophenol antibodies for effector activity. This approach of using HDAds encoding bNAbs may also be combined with latency reversal agents, in order to clear out infected cells. The results of these investigations should accelerate the use of bNAbs as an adjunct to ART in the treatment of HIV disease, with the potential for functional eradication due to elimination or prevention of reactivation of persistently-infected cells.