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感染的控制已经发生了革命性的变化，它显著降低了大约70%的进行性长期HIV-1感染患者的病毒负担并部分恢复了宿主免疫力。尽管取得了这一进展，但HAART疗法可能具有剧毒，不能消除宿主体内的HIV-1储存库。因此，在HAART停止后，HIV-1的高水平复制和致病性后遗症往往会恢复。我们认为这部分是由于对病毒复制的免疫控制不完全。我们假设在HAART期间更有效地控制HIV-1感染可以通过工程树突状细胞（dc）诱导更有效和增强广度的抗HIV-1 CD8+和CD4+ T细胞免疫反应来实现。由匹兹堡大学研究人员组成的多学科联盟，与我们的商业合作伙伴ImmunoSite一起，提出了一种创新的免疫治疗策略，即用来自同一宿主（“自体”HIV-1）的病毒对dc进行体外工程。在项目1中，我们建议在恒河猴HAART模型中评估负载由腺病毒载体编码的SIV抗原的dc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对Th1反应极化的各种新策略。在项目3中，我们将通过I期临床试验推进我们的CD8+和CD4+ T细胞刺激模型，该模型是通过装载来自临床前工作的自体HIV-1感染的凋亡细胞的dc刺激CD8+和CD4+ T细胞。这些项目在概念上和操作上相互作用，合作改进DC活化和自体抗原向T细胞递呈的方法。载体core B将为项目1和项目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。成像中心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的临床试验提供高度创新的、gmp级的DC和T细胞体外处理的新技术。我们相信，这种新的免疫治疗策略理想地实现了NIAID临床前/临床综合项目的目的。

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.