COMBINATION GENE TRANSFER, ANTIVIRAL TREATMENT & IMMUNOSTIMULATION FOR HIV+

组合基因转移、抗病毒治疗

• 批准号: 6201447
• 负责人: Gary J Nabel
• 金额: $ 22.01万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-01 至 2000-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6201447
• 关键词: AIDS therapy; HIV infections; antiAIDS agent; cell line; chemokine; child (0-11); clinical research; clinical trials; combination therapy; cytokine receptors; gene expression; gene therapy; genetic transduction; helper T lymphocyte; human immunodeficiency virus 1; human subject; human therapy evaluation; immunotherapy; interleukin 2; pediatric AIDS; receptor expression; transfection /expression vector; virus genetics; virus protein; virus replication

Advances in the pharmacologic treatment of HIV infection have led to a remarkable reduction in viral load for many HIV-infected individuals. Despite the success of antiviral drugs, a significant percentage of patients remain resistant or intolerant to them, and virus or low level persistent viral replication may continue to damage the immune system. A major challenge in AIDS research is to augment immune function in infected patients and eliminate residual virus in those with ow viral loads. In this project, combination antiviral gene therapy, together with anti- retroviral drugs and immunostimulatory treatments, will be analyzed. The genes transfer approaches are based upon expression of intracellular gene products which inhabit viral replication. We have previously shown that an essential viral protein, Rev M10, prolongs the survival of T cells transduced with non-viral and retroviral vectors in HIV-infected subjects. In this study, Rev M10 will be explored in combination with other anti- retroviral genes which affect virus entry. First, the efficacy of targeting relevant chemokine receptors, or other genes which affect the afferent phase of the virus life cycle, will be compared to Rev M10, alone or in combination. A second aim is to develop improved vector production systems. Such retroviral delivery systems and evolving lentiviral vectors will be adapted for human trials in collaboration with Drs. Kohn (Project 1) and Nolan (Project 3). In collaboration with Project 4, the immunogenicity of these antiviral genes and their effects on immune function in animal models or in human cells be performed, particularly those involving inhibition of chemokine receptor function. Finally, the optimal combination of antiviral genes will be used in clinical studies in HIV-infected subjects, and the engraftment of genetically-modified cells in the presence or absence of anti-retroviral therapy and/or immunostimulation will be explored. These studies will be performed both in adult and pediatric AIDS patients, in collaborations with Drs. Kohn and Wara, in an expansion of previous work supported by SPIRAT. Together, these studies will explore the potential for gene transfer to complement existing antiviral pharmacologic and immune stimulation treatments, to promote immune reconstitution, and provide further information about the effects of these treatments on lymphocyte survival in HIV infection. Development of such combination approaches may ultimately enhance long- term immune function and contribute to elimination of the residually infected cells in patients during treatment of HIV infection.

HIV感染的药物治疗的进展导致了 许多HIV感染者的病毒载量显著降低。 尽管抗病毒药物取得了成功， 患者对它们仍有耐药性或不耐受，病毒或低水平 持续的病毒复制可能继续损害免疫系统。一 艾滋病研究的主要挑战是增强感染者的免疫功能， 患者，并消除那些低病毒载量的残留病毒。在 该项目联合抗病毒基因治疗， 逆转录病毒药物和免疫刺激治疗，将进行分析。的 基因转移方法基于细胞内基因的表达 抑制病毒复制的产品。我们之前已经证明， 关键病毒蛋白Rev M10抑制T细胞存活 用非病毒和逆转录病毒载体在HIV感染的受试者中转导。 在本研究中，将探索Rev M10与其他抗- 影响病毒进入的逆转录病毒基因。第一，功效 靶向相关的趋化因子受体，或其他基因， 病毒生命周期的传入阶段将与单独的Rev M10进行比较 或组合。第二个目标是开发改进的载体生产 系统.这种逆转录病毒递送系统和进化中的慢病毒载体 将与Kohn博士合作进行人体试验（项目 1)Nolan（项目3）与项目4合作， 这些抗病毒基因免疫原性及其对免疫应答的影响 在动物模型中或在人细胞中发挥功能，特别是 涉及抑制趋化因子受体功能的那些。最后 抗病毒基因的最佳组合将用于临床研究， HIV感染者，以及基因修饰细胞的植入 在存在或不存在抗逆转录病毒治疗的情况下，和/或 将探索免疫刺激。这些研究将在以下两个方面进行： 在成人和儿童艾滋病患者中，与Kohn博士合作， Wara，在SPIRAT支持的先前工作的扩展中。在一起， 这些研究将探索基因转移的潜力， 现有的抗病毒药理学和免疫刺激治疗， 促进免疫重建，并提供有关 这些治疗对HIV感染中淋巴细胞存活的影响。 这种结合方法的发展最终可能会提高长期的， 长期的免疫功能，并有助于消除残留的 在治疗HIV感染的过程中感染细胞。