Dendritic Cell-Based Immunotherapy for HIV Infection

描述(由申请人提供)：随着有效的联合药物疗法(HAART)的出现，HIV-1感染的控制已经发生了革命性的变化，这种疗法大大降低了病毒负担，并在大约70%的进行性、长期的HIV-1感染患者中部分恢复了宿主免疫。尽管取得了这一进展，HAART方案可能是剧毒的，并且不能消除宿主中的HIV-1宿主。因此，一旦停止HAART，往往会恢复高水平的艾滋病毒-1复制和致病后遗症。我们认为，这在一定程度上是由于对病毒复制的免疫控制不完整。我们假设，在HAART期间，通过工程树突状细胞(DC)诱导更强大和更广泛的抗HIV-1 CD8+和CD4+T细胞免疫反应，可以更有效地控制HAART期间的HIV-1感染。我们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免疫网站一起，提出了一种创新的免疫治疗策略，通过体外工程将来自同一宿主的病毒(“自体”HIV-1)的DC。在项目1中，我们建议评估由腺病毒载体编码的SIV抗原负载的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由裸质粒编码的自体HIV-1在小鼠和体外人类模型中转染树突状细胞，包括各种新的树突状细胞极化Th1反应的策略。在项目3中，我们将通过I期临床试验推进我们的模型，即负载自体HIV-1感染的DC和临床前工作中的凋亡细胞的DC刺激CD8+和CD4+T细胞。这些项目通过合作改进DC激活和自体抗原呈递给T细胞的方法，在概念和操作上相互作用。载体核心B将为项目1和2提供病毒和细胞因子的表达载体，并为项目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。通过为项目2中的临床前研究和项目3中的临床试验提供GMP级DC和T细胞的体外处理的高度创新的新技术，免疫站点将引领DC CORE D。我们相信，这一新的免疫治疗策略理想地实现了NIAID临床前/临床综合计划的意图。

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.