Dendritic Cell-Based Immunotherapy for HIV Infection

描述（由申请人提供）：随着强效联合药物治疗（HAART）的出现，HIV-1感染的控制发生了革命性变化，HAART显著降低了病毒负荷，并在约70%的进行性长期HIV-1感染患者中部分恢复了宿主免疫力。尽管取得了这一进展，HAART方案可能是高毒性的，不能消除宿主中的HIV-1储存库。因此，在停止HAART后，经常会恢复高水平的HIV-1复制和致病性后遗症。我们认为，这部分是由于病毒复制的免疫控制不完全。我们假设，在HAART期间，可以通过工程化树突状细胞（DC）诱导更有效和增强的抗HIV-1 CD 8+和CD 4 + T细胞免疫应答的广度来实现对HIV-1感染的更有效控制。我们的匹兹堡大学研究人员多学科联盟与我们的商业合作伙伴ImmunoSite一起，提出了一种创新的免疫策略，即用来自同一宿主（“自体”HIV-1）的病毒对DC进行体外工程改造。在项目1中，我们建议评估负载有腺病毒载体编码的SIV抗原的DC在恒河猴HAART模型中的佐剂作用。在项目2中，我们将这一概念扩展到小鼠和体外人类模型中由裸DNA质粒编码的自体HIV-1转染的DC，包括DC极化Th 1应答的各种新策略。在项目3中，我们将通过I期临床试验推进我们的模型，该模型通过负载自体HIV-1感染的凋亡细胞的DC刺激CD 8+和CD 4 + T细胞。这些项目通过合作改进DC活化和自体抗原呈递给T细胞的方法，在概念上和操作上相互作用。载体核心B将为项目1和2提供病毒和细胞因子表达载体，为项目3提供新的抗原肽衍生方法。成像核心C将为每个项目提供最先进的荧光显微镜。ImmunoSite将领导DC核心D，为项目2的临床前研究和项目3的临床试验提供GMP级的DC和T细胞体外处理的高度创新的新技术。我们认为，这种新型免疫治疗策略理想地实现了NIAID综合临床前/临床计划的意图。

DESCRIPTION (provided by applicant): Control of HIV-1 infection has been revolutionized with the advent of potent combination drug therapy (HAART) that dramatically lowers viral burden and partially restores host immunity in approximately 70% of patients with progressive, long term HIV-1 infection. In spite of this advance, HAART regimens can be highly toxic and cannot eliminate reservoirs of HIV-1 in the host. Thus, upon cessation of HAART, there is often a resumption of high levels of HIV-1 replication and pathogenic sequelae. We propose that this is in part due to incomplete immune control of virus replication. We hypothesize that more efficient control of HIV-1 infection during HAART can be achieved by engineering dendritic cells (DCs) to induce a more potent and enhanced breadth of anti-HIV-1 CD8+ and CD4+ T cell immune responses. Our multidisciplinary consortium of University of Pittsburgh investigators, together with our commercial partner, ImmunoSite, propose an innovative immunotherapeutic strategy by ex vivo engineering of DCs with virus derived from the same host ("autologous" HIV-1). In Project 1, we propose to assess DCs loaded with SIV antigen encoded by adenovirus vectors for adjuvant effects in the rhesus macaque HAART model. In Project 2, we extend this concept to DCs transfected by autologous HIV-1 encoded by naked DNA plasmids in mice and in vitro human models, including various new strategies for polarization of Th1 responses by DCs. In project 3, we will advance our model of stimulation of CD8+ and CD4+ T cells by DCs loaded with autologous HIV-1 infected, apoptotic cells from preclinical work through a phase I clinical trial. These projects interact conceptually and operationally by collaborating on improving methods of DC activation and autologous antigen presentation to T cells. Vector core B will provide viral and cytokine expressing vectors for projects 1 and 2, and a new antigenic peptide derivation method for project 3. Imaging core C will provide state-of-the-art fluorescent microscopy for each project. ImmunoSite will lead DC core D by providing highly innovative, new technology for GMP-grade, ex vivo processing of DCs and T cells for preclinical studies in project 2, and the clinical trial in project 3. We believe that this novel immunotherapy strategy ideally fulfills the intent of the NIAID Integrated Preclinical/Clinical Program.