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Ablation of HIV-1 infected cells by sustained bNAb expression from B-cells

B 细胞持续表达 bNAb 消除 HIV-1 感染细胞

基本信息

批准号：
10614646
负责人：
Koki Morizono
金额：
$ 45.36万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-07 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10614646
关键词：
Ablation Animal Model Antibodies Antibody Formation Antibody-Producing Cells Antigen Presentation Antigen Targeting Applications Grants Autoantigens Autoimmune Diseases Autoimmunity B Cell Proliferation B-Cell Antigen Receptor B-Cell Receptor Binding B-Lymphocytes Biodistribution Blood Bone Marrow Cell Differentiation process Cell Proliferation Cell-Mediated Cytolysis Cells Cellular Immunity Chromosomes Chronic Clinical Trials Collaborations Communicable Diseases Complement Complement Activation Complement-Dependent Cytotoxicity Dendritic Cells Disease Dose Drug Kinetics Elements Experimental Designs Factor IX Gene Transduction Agent Genes Genetic Engineering Genetic Recombination Genome Gut associated lymphoid tissue HIV HIV-1 Half-Life Hemophilia A Human Humoral Immunities Immune response Immunology Infection Infection prevention Inflammation Infusion procedures Intramuscular Lentivirus Vector Longevity Lymphoid Tissue Mediating Membrane Memory B-Lymphocyte Methods Mus Muscle Mutation Physiological Plasma Cells Proliferating Receptor Signaling Recombinants Safety Serum Site Structural Protein Suicide Therapeutic Time Tissues Transgenes Viral Viremia Virus Virus Diseases Virus Replication anti-viral efficacy antibody mimetics antibody-dependent cell cytotoxicity cancer cell cell type cellular transduction chronic infection complement system cost cytotoxicity engineered T cells gene product gene therapy hematopoietic tissue humanized mouse immunoreaction in vivo inhibitor intravenous administration lentivirally transduced lymph nodes mouse model neutralizing antibody nonhuman primate novel therapeutic gene transgene expression vector

项目摘要

Project 2: Summary/Abstract Broadly neutralizing antibodies (bNAbs) against HIV-1 can inhibit viral replication by two distinct mechanisms. One is the neutralization of virus, which prevents infection. The other is its ability to kill HIV-1 infected cells through activation of complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC). Thus, bNAbs have the potential to not only inhibit new viral infection cycles but also eliminate chronically infected cells, which are necessary for cure of the HIV-1 disease. However, the serum concentrations of the antibodies must be kept at therapeutic levels for long periods of time to eliminate HIV-1-infected cells, because persistently infected cells reside in the deep tissue. Therefore, multiple administrations of the antibodies are required, which could be expensive and labor-intensive. In addition, administration of recombinant bNAbs can raise host immune reactions to the bNAbs, leading to loss of neutralization and cytotoxicity activities of bNAbs and shortening their halflife. Gene therapy vectors, especially lentiviral/oncoretroviral vectors that integrate their transgene into host chromosomes, can produce bNAbs in vivo for long periods. But immune reactions against the bNAbs can still decrease the antiviral efficacy of bNAbs and shorten the duration of bNAb expression. B cells physiologically express wide varieties of valuable antibody regions generated by recombination and mutations in genes. B cells are known to induce tolerance to the valuable regions. This ability of B cells was previously used to induce tolerance to self-antigens for therapy of autoimmune diseases and coagulation factor IX for treatment of hemophilia. Therefore, transduction of B cells with bNAb expressing vectors is likely to generate long-term bNAbs without inducing immune reactions to the bNAbs. We have developed lentiviral vectors that can specifically transduce desired target cell types after systemic administration. By specific transduction of B cells by this lentiviral vector, we will attempt to express bNAbs for long periods of time by avoiding immune reactions against bNAbs. We will also attempt to prolong the duration of bNAb expression by differentiating transduced B-cells to long-lived plasma cells and memory B-cells, which have long life-span. We will then investigate if bNAbs expressed from B-cells can eliminate HIV-1-infected cells in mice. Since commonly used mice do not have normal complement, we will use a novel type of mouse model that has an intact complement system for full CDC activity of the bNAb. We will next investigate whether bNAbs expressed from B cells and T cells engineered to express anti-HIV-1 transgene can synergistically eliminate HIV-1 infected cells in the B cells. Lastly, we will investigate whether systemic administration of our B-cell targeting lentiviral vector can specifically transduce B cells in non-human primates (NHP) by analyzing biodistribution and cell types of transduced cells. We will also investigate the pharmacokinetics of and immune reactions to bNAbs expressed in NHP. These experiments are designed to develop a novel bNAb-based gene therapeutic approach, which can be applicable to other infectious diseases.

项目2：摘要/摘要