Induction of Immunity by Non-Replicating HIV-1

非复制型 HIV-1 诱导免疫

• 批准号: 7875093
• 负责人: Nina Bhardwaj
• 金额: $ 36.11万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7875093
• 关键词: AIDS Vaccines; Affect; Aldrithiol-2; Anti-Retroviral Agents; Antigen-Presenting Cells; Antigens; Autologous; Autologous Dendritic Cells; CD8B1 gene; Cell physiology; Cells; Chinese People; Clinical Research; Defective Viruses; Dendritic Cells; Epitopes; Exposure to; HIV; HIV Infections; HIV-1; Human; Immune; Immune response; Immunity; Immunization; In Vitro; Individual; Institutes; Institution; Interruption; Laboratories; Life; Lymphocyte; Macaca mulatta; Membrane Proteins; Methodology; Methods; Morbidity - disease rate; Outcome Measure; Patients; Peptides; Pharmacotherapy; Phase; Physiologic pulse; Plasma; Practice Guidelines; Preparation; Procedures; Process; RNA; Reading; SIV; Safety; Sterility; System; T-Cell Activation; T-Lymphocyte; Therapeutic; Tissues; Vaccines; Viral; Viremia; Virion; Virus; base; cohort; immunogenicity; macrophage; meetings; monocyte; mortality; primary outcome; programs; quality assurance; reconstitution; response; secondary outcome

Although the institution of anti-retroviral therapy (ART) has reduced morbidity and mortality from HIV infection, immune reconstitution is incomplete, virus persists in tissue reservoirs and rebound viremia occurs when treatment is halted. Recent findings that intermittent compliance with drug therapy can stimulate T cell responses has led to the concept that low-level antigenic stimulation through re-exposure to virus, or boosting of T cell responses via immunization, may facilitate control of viral replication as an adjunct to ART. An effective way to generate human T cell responses is by presenting antigens on dendritic cells (DCs), a system of antigen presenting cells (APCs) that stimulate innate and acquired immune responses. DCs pulsed with live or chemically inactivated (Aldrithiol-2 treated) HIV or SIV, efficiently induce HIV-specific CD4+ and CD8+ T cell responses from human cells in vitro. Aldrithiol-2 (AT-2) inactivates HIV infectivity without affecting the conformational and functional integrity of virion surface proteins. DCs pulsed with AT-2 inactivated SIV induced long term control of viremia in Chinese rhesus macaques chronically infected with SIVmac251. Furthermore, we have established the safety and immunogenicity of DCs in healthy individuals and more recently in HIV+ individuals. Based on these findings, we will determine whether DCs pulsed with AT-2 inactivated-HIV induce therapeutic immune responses in a cohort of chronically infected HIV+ individuals. The specific aims are to: (1) optimize the capture, processing and presentation of AT-2 treated HIV by human DCs in vitro, as a prelude to clinical studies; (2) develop the methodology required to prepare sterile AT-2 inactivated autologous HIV from patients'monocytes on a level which meets regulatory requirements, and (3) to establish the immunogenicity of DCs pulsed with autologous AT-2 inactivated HIV in an ART suppressed, chronically infected HIV+ cohort. These studies will help determine whether non-replicating HIV, when delivered on DCs, induces durable CD4 and CD8 responses which facilitate control of viral replication, even after termination of ART.

尽管抗逆转录病毒疗法（ART）的建立降低了艾滋病毒的发病率和死亡率 感染，免疫重建不完全，病毒在组织储存库中持续存在，病毒血症反弹 当治疗停止时发生。最近发现间歇性依从药物治疗可以 刺激 T 细胞反应引出了这样一个概念：通过重新暴露于低水平的抗原刺激 病毒或通过免疫增强 T 细胞反应，可能有助于控制病毒复制 艺术的辅助。产生人类 T 细胞反应的有效方法是在树突状细胞上呈递抗原 细胞 (DC)，刺激先天和获得性免疫的抗原呈递细胞 (APC) 系统 回应。 DCs 用活的或化学灭活的（Aldrithiol-2 处理的）HIV 或 SIV 进行有效脉冲 在体外诱导人类细胞的 HIV 特异性 CD4+ 和 CD8+ T 细胞反应。 Aldrithiol-2 (AT-2) 灭活 HIV 感染性而不影响病毒粒子表面的构象和功能完整性 蛋白质。用 AT-2 灭活的 SIV 脉冲的 DC 诱导中国恒河猴病毒血症的长期控制 慢性感染 SIVmac251 的猕猴。此外，我们还建立了安全和 DCs在健康个体和最近的HIV+个体中的免疫原性。基于这些 研究结果，我们将确定用 AT-2 灭活的 HIV 脉冲的 DC 是否会诱导治疗性免疫 一组慢性感染艾滋病毒+个体的反应。具体目标是：（1）优化 人类 DC 在体外捕获、处理和呈现 AT-2 处理的 HIV，作为临床前奏 研究； (2) 开发从细胞中制备无菌 AT-2 灭活自体 HIV 所需的方法 患者的单核细胞水平符合监管要求，并且 (3) 建立 在长期抑制的 ART 中用自体 AT-2 灭活 HIV 脉冲的 DC 的免疫原性 感染艾滋病毒+队列。这些研究将有助于确定非复制性艾滋病毒在交付时是否 DCs 诱导持久的 CD4 和 CD8 反应，有助于控制病毒复制，即使在 ART 的终止。