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（由适用提供）：尽管现代疗法已经显着改善了艾滋病毒/艾滋病（PLWHA）患者的前景，但他们无法治愈感染，这使这些人终生致力于对昂贵的抗逆转录病毒药物的承诺。同样，这些治疗方法并不能完全恢复健康，也没有解决与艾滋病毒呈阳性有关的负面社会问题，包括污名和与犯罪有关的问题。因此，安全有效的HIV治疗的发展将大大改善PLWHA的生活。治愈艾滋病毒感染的主要障碍是建立隐藏或“潜在”病毒的储层，该病毒逃避了免疫系统，如果一个人停止抗逆转录病毒疗法，可以重新种植感染。在这个项目中，我们 正在采用一种新颖的方法来设计免疫系统目标并消除这种潜在的HIV水库。该人体具有几种类型的免疫复发，有可能导致根除HIV储层，包括i）涉及杀手T细胞的反应（或CD8 T细胞反应），涉及一种细胞，涉及一种可以识别和杀死病毒感染细胞的细胞II）II）ii）抗体反应（从某种类型的细胞中，可以与其他类型的细胞结合并在自然中结合），并在自然中结合therus，并在自然中结合血液中的病毒，并在病毒中结合）杀手反应，涉及另一种专门杀死用抗体标记的感染细胞的细胞。 W将通过赋予生产HIV特异性抗体的能力来赋予这些系统之间的协同作用。这种抗体的产生只有在这些杀手T细胞遇到HIV感染的细胞，或者当它们被药物刺激时也将HIV从隐藏中推出，“潜伏期逆转剂或LRA”刺激时，才会严格控制这种抗体。这项工作的最终目的是开发一种治疗性干预措施，在其中使用这些工程细胞和LRA对PLWHA进行处理。 LRA既将暴露于HIV储层，又会触发对这些未掩盖的靶细胞的三方免疫攻击，从而导致病毒清除，并希望能够治愈。