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；

• 批准号: 9049767
• 负责人: Conrad Russell Young Cruz
• 金额: $ 26.25万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9049767
• 关键词: AIDS/HIV problem; Address; Adherence; Adoptive Transfer; Anti-Retroviral Agents; Antibodies; Antibody Formation; Antiviral Agents; Autologous; B-Lymphocytes; Binding; Biological Assay; Blood; CD4 Positive T Lymphocytes; CD8B1 gene; Cancer Patient; Cell physiology; Cells; Cytomegalovirus; Development; 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; Left; Life; Maintenance; Measures; Natural Killer Cells; Patients; Penetration; Peptide Signal Sequences; Persons; Pharmaceutical Preparations; Phase; Process; Production; Seeds; Series; Site; Specificity; System; T cell response; T-Lymphocyte; Testing; Therapeutic Intervention; Time; Tissues; Variant; Viral; Viral Antigens; Viral reservoir; Virus; Virus Diseases; Work; antibody-dependent cell cytotoxicity; antiretroviral therapy; antiviral immunity; arm; cell killing; cell type; cellular engineering; curative treatments; design; epigenetic drug; humanized mouse; improved; in vivo; interest; killer T cell; killings; mouse model; neutralizing antibody; novel; novel strategies; prevent; promoter; public health relevance; purge; reconstitution; response; social; social stigma

 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.

 描述（由申请人提供）：尽管现代疗法极大地改善了艾滋病毒/艾滋病患者 (PLWHA) 的前景，但它们无法治愈感染，使这些人终生承受昂贵的抗逆转录病毒药物的负担。很明显，这些治疗方法并不能完全恢复健康，也不能解决与艾滋病毒呈阳性相关的负面社会问题，包括耻辱和与刑事定罪相关的问题。因此，开发安全有效的艾滋病毒治疗方法将极大地改善艾滋病病毒感染者的生活。治愈艾滋病毒感染的一个主要障碍是建立隐藏或“潜伏”病毒库，这些病毒可以逃避免疫系统，如果个人停止抗逆转录病毒治疗，可能会重新传播感染。在这个项目中，我们 正在寻求一种新方法来设计免疫系统目标并消除这种潜在的艾滋病毒储存库。人体有几种类型的免疫反应，有可能有助于根除艾滋病毒储存库，包括 i) 杀伤性 T 细胞反应（或 CD8 T 细胞反应），涉及一种可以识别和杀死病毒感染细胞的细胞 ii) 抗体反应（来自不同类型的细胞，B 细胞），它既可以结合并灭活血液中的病毒，也可以结合并标记病毒感染的细胞 iii) 自然杀手 反应，涉及另一种类型的细胞，专门杀死已用抗体标记的受感染细胞。 W 将通过赋予 HIV 特异性杀伤 T 细胞产生 HIV 特异性抗体的能力，在这些系统之间建立协同作用。这种抗体的产生将受到严格控制，只有当这些杀伤性 T 细胞遇到感染 HIV 的细胞，或者受到一种也能将 HIV 隐藏起来的药物（一种“潜伏期逆转剂”或 LRA）刺激时，才会发生这种抗体的产生。这项工作的最终目标是开发一种治疗干预措施，用这些工程细胞和 LRA 治疗 PLWHA。 LRA 既会暴露 HIV 储存库，也会触发对这些暴露的目标细胞的三方免疫攻击，从而清除病毒并有望治愈。