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Engineered CTL with Inducible Ab Secretion; a Tripartite attack on HIV Reservoirs

具有可诱导抗体分泌的工程 CTL；

基本信息

批准号：
9768949
负责人：
Conrad Russell Young Cruz
金额：
$ 51.08万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-01-01 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9768949
关键词：
AIDS/HIV problem Address Adherence Adoptive Transfer Anatomy Anti-Retroviral Agents Antibodies Antibody Formation Antiviral Agents Autologous B-Lymphocytes Binding Biological Assay Blood CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cancer Patient Cell physiology Cells Cytomegalovirus Cytotoxic T-Lymphocytes Development Drug Exposure Engineering Fc domain Frequencies HIV HIV Infections HIV Seropositivity Health Heavy-Chain Immunoglobulins Human Herpesvirus 4 IgG1 Immune Immune response Immune system Immunodeficient Mouse In Vitro Individual Infection Infusion procedures Label Latent Virus Maintenance Measures Modernization Natural Killer Cells Patients Penetration Peptide Signal Sequences Persons Pharmaceutical Preparations Phase Process Production Seeds Series Specificity System T cell response T-Lymphocyte Testing Therapeutic Intervention Time Tissues Variant Viral Viral Antigens Viral reservoir Virus Virus Diseases Virus Latency Work antibody-dependent cell cytotoxicity antiretroviral therapy antiviral immunity arm cell killing cell type curative treatments design epigenetic drug genetically modified cells humanized mouse immunoengineering improved in vivo interest mouse model neutralizing antibody novel novel strategies prevent promoter public health relevance purge reconstitution response social social stigma synergism viral rebound

项目摘要

DESCRIPTION (provided by applicant): Although modern therapies have dramatically improved the outlooks for people living with HIV/AIDS (PLWHA) they are unable to cure infection, leaving these individuals burdened by a lifelong commitment to expensive antiretroviral medication. It has also become clear that these treatments do not fully restore health, nor do they address the negative social issues associated with being HIV positive, including stigma and issues related to criminalization. The development of a safe and effective HIV cure would thus greatly improve the lives of PLWHA. A major obstacle to curing HIV infection is the establishment of reservoirs of hidden or `latent' virus which evade the immune system and can re-seed infection if an individual stops antiretroviral therapy. In this project, we are pursuing a novel approach to engineer the immune system target and eliminate this latent HIV reservoir. The body has several types of immune responses with the potential to contribute to the eradication of HIV reservoirs including i) the killer T-cell response (or CD8 T-cell response) involving a type of cell that can recognize and kill virus infected cells ii) the antibod response (from a different type of cell, B cells) which can both bind to and inactivate virus in th blood and can bind to and label virus-infected cells iii) the natural killer response, involving another type of cell that specifically kills infected cells that have been labeled with antibody. W will create synergy between these systems by endowing HIV-specific killer T-cells with the ability to produce HIV-specific antibodies. This production of antibodies will be tightly controlle to only occur when these killer T- cells either encounter an HIV-infected cell, or when they are stimulated by a drug that also pushes HIV out of hiding, a `latency reversing agent or LRA'. The ultimate aim of this work is to develop a therapeutic intervention where PLWHA are treated with both these engineered cells and LRAs. The LRAs will both expose HIV reservoirs and trigger this tripartite immune attack on these unmasked target cells, leading to viral clearance and hopefully to cures.