Immunotherapy with Autologous HIV-Loaded Dendritic Cells

在慢性感染患者中控制HIV-1感染已经发生了革命性的变化 抗逆转录病毒疗法(HAART)。然而，长期的HAART是有毒的，而且不完全恢复 抗HIV-1T细胞功能；去除HAART通常也会导致病毒载量的快速增加。因此， 我们推测，针对自体病毒的免疫治疗可以导致适当的控制。 在HAART期间残留的HIV-1感染。我们假设树突状细胞(DC)装载有 感染自体HIV-1的自体细胞可以作为有效的免疫原 用于激活针对多种自体HIV-1抗原的CD8*和CD4？T细胞。 这是基于我们最近的发现，携带HIV-1感染的DC，凋亡细胞诱导CD8* 以及体外对HIV-1特异的CD4*T细胞反应。为了进一步完善这一模式，我们建议 通过比较免疫原性和抗原特异性的广度来扩展我们的临床前研究 自体HIV-land成熟DC负载凋亡细胞的体外诱导 不同的细胞因子环境。我们将使用这种体外模型来确定其安全性和免疫原性。 体外加载的自体DC作为HIV-1感染成人在HAART中作为HIV-1免疫原的研究 I期临床试验。最后，我们建议监测CD8？和CD4？T细胞对 并表征体外免疫前后病毒进化的变化。 这种DC-凋亡细胞模型可能是一种理想的免疫原，因为它包含所有形式的HIV-1蛋白 并可作为自体病毒治疗性免疫的载体。

Control of HIV-1 infection in chronically infected patients has been revolutionized by highly active antiretrovirai therapy (HAART). However, long term HAART is toxic and there is incomplete recovery of anti-HIV-1 T cell function; removal of HAART usually also results in rapid increases in viral load. Thus, we postulate that immunotherapy specifically directed to autologous virus can lead to adequate control of residual HIV-1 infection during HAART. We hypothesize that dendritic cells (DCs) loaded with apoptotic, autologous cells that are infected with autologous HIV-1 can serve as potent immunogens for activation of both CD8* and CD4 ¿ T cells specific for a broad range of autologous HIV-1 antigens. This is based on our recent findings that DCs loaded with HIV-1 infected, apoptotic cells induce CD8* and CD4* T cell responses specific for HIV-1 in vitro. To further refine this model, we propose to expand our preclinical studies by comparing the immunogenicity and the breadth of antigen specificity induced ex vivo by DCs loaded with apoptotic cells infected with autologous HIV-land DCs matured by different cytokine milieus. We will use this ex vivo model for determining the safety and immunogenicity of ex vivo loaded, autologous DCs as an HIV-1 immunogen in HIV-1 infected adults on HAART in a phase I clinical trial. Finally, we propose to monitor the breadth of CD8 ¿ and CD4 ¿ T cell responses to autologous HIV-1 and characterize viral evolutionary changes before and after ex vivo immunization. This DC-apoptotic cell model may be an ideal immunogen in that it contains all forms of HIV-1 proteins and can be used as a vehicle for therapeutic immunization with autologous virus.