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Induction of Immunity by Non-Replicating HIV-1

非复制型 HIV-1 诱导免疫

基本信息

批准号：
8744626
负责人：
Nina Bhardwaj
金额：
$ 22.12万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-12-19 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8744626
关键词：
Affect Antigen-Presenting Cells Antigens Antiviral Agents Autologous Autologous Dendritic Cells CD8B1 gene Cell Maturation Cells Chinese People Clinical Research Controlled Study Cyclic GMP Cytotoxic T-Lymphocytes Defective Viruses Dendritic Cells Down-Regulation Exposure to Funding Goals Grant HIV HIV Infections HIV-1 Helper-Inducer T-Lymphocyte Human Hurricane IL2 gene Immune Immune response Immunity Immunization In Vitro Individual Inflammatory Institution Laboratories Life Lymphoid Macaca mulatta Membrane Proteins Methodology Morbidity - disease rate Organ Organism Pathway interactions Patients Peripheral Pharmacotherapy Physiologic pulse Preparation Procedures Process SIV Safety Sterility System T cell response T-Lymphocyte Therapeutic Tissues Up-Regulation Vaccination Vaccines Viral Viremia Virion Virus Virus Diseases antigen processing antiretroviral therapy base cohort cost cytokine immunogenicity meetings monocyte mortality pre-clinical quality assurance receptor reconstitution response therapeutic vaccine validation studies

项目摘要

Although the institution of antiretroviral 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 CD4+ and CD8+ 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 (Aldrithiol2 treated) HIV or SIV (simian immunodeficiency virus), efficiently induce HIV-specific CD4+ and CD8+ T cell responses from human cells in vitro. Aldrithiol2 (AT2) inactivates HIV infectivity without affecting the conformational and functional integrity of virion surface proteins. DCs pulsed with AT2 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 AT2 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 AT2 treated HIV by human DCs in vitro, as a prelude to clinical studies; (2) develop the methodology required to prepare sterile AT2 inactivated autologous HIV from patients’ monocytes on a level which meets regulatory requirements, and (3) to establish the safety and immunogenicity of DCs pulsed with autologous AT2 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.

虽然抗逆转录病毒疗法（ART）降低了艾滋病毒感染的发病率和死亡率，但免疫重建不完全，病毒在组织库中持续存在，治疗停止时会发生反弹性病毒血症。最近的研究发现，间歇性依从药物治疗可以刺激T细胞应答，这导致了这样的概念，即通过再次暴露于病毒的低水平抗原刺激，或通过免疫增强T细胞应答，可以促进控制病毒复制作为ART的辅助。产生人CD 4+和CD 8 + T细胞应答的有效方法是通过在树突状细胞（DC）上呈递抗原，一种刺激先天性和获得性免疫反应的抗原呈递细胞（APC）系统。用活的或化学灭活的（Aldrithiol 2处理的）HIV或SIV（猿猴免疫缺陷病毒）脉冲的DC在体外有效地诱导来自人细胞的HIV特异性CD 4+和CD 8 + T细胞应答。Aldrithiol 2（AT 2）灭活HIV感染性，而不影响病毒体表面蛋白的构象和功能完整性。用AT 2灭活的SIV致敏的DC诱导SIVmac 251慢性感染的中国恒河猴的病毒血症的长期控制。此外，我们已经在健康个体和最近在HIV+个体中确定了DC的安全性和免疫原性。基于这些发现，我们将确定是否与AT 2灭活的HIV脉冲DC诱导治疗性免疫应答在一个队列的慢性感染的HIV+的个人。具体目标是：（1）优化体外人DC对AT 2处理的HIV的捕获、加工和呈递，作为临床研究的前奏;（2）开发从患者的单核细胞制备无菌AT 2灭活的自体HIV所需的方法，达到符合法规要求的水平;和（3）建立ART抑制的DC中用自体AT 2灭活的HIV脉冲的安全性和免疫原性，慢性感染HIV+的队列。这些研究将有助于确定非复制型HIV在DC上递送时是否会诱导持久的CD 4和CD 8反应，从而促进病毒复制的控制，即使在ART终止后也是如此。