COMBINATION GENE TRANSFER, ANTIVIRAL TREATMENT & IMMUNOSTIMULATION FOR HIV+

HIV感染的药物治疗的进展导致了 许多艾滋病毒感染者的病毒载量显著减少。 尽管抗病毒药物取得了成功，但仍有相当大比例的 患者仍然对它们有抵抗力或不耐受，病毒水平或低水平 持续的病毒复制可能会继续损害免疫系统。一个 艾滋病研究的主要挑战是增强感染者的免疫功能 并在病毒载量较低的患者中消除残留病毒。在……里面 该项目，结合抗病毒基因治疗，与抗病毒 将对逆转录病毒药物和免疫刺激治疗进行分析。这个 基因转移的方法是基于细胞内基因的表达 滋生病毒复制的产品。我们之前已经展示了一个 必需病毒蛋白REV M10延长T细胞存活时间 在艾滋病毒感染者中转导非病毒和逆转录病毒载体。 在这项研究中，M10修订版将与其他抗病毒药物结合使用 影响病毒进入的逆转录病毒基因。第一，药效。 靶向相关的趋化因子受体，或其他影响 病毒生命周期的传入阶段，将单独与M10版本进行比较 或者组合在一起。第二个目标是发展改良的媒介生产。 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(Project 1)和诺兰(项目3)。在与项目4的合作下， 这些抗病毒基因的免疫原性及其对免疫的影响 在动物模型或人类细胞中执行的功能，特别是 涉及趋化因子受体功能抑制的那些。最后， 抗病毒基因的最佳组合将用于临床研究 艾滋病毒感染者和转基因细胞的植入 在存在或不存在抗逆转录病毒治疗和/或 将探索免疫刺激作用。这些研究将同时进行 在成人和儿童艾滋病患者中，与Kohn博士和 WARA，在SPIRAT支持的先前工作的扩展中。一起， 这些研究将探索基因转移来补充 现有的抗病毒药物和免疫刺激疗法，以 促进免疫重建，并提供有关 这些治疗方法对HIV感染患者淋巴细胞存活的影响。 这种组合方法的开发最终可能会增强长期的 具有长期免疫功能，有助于消除残留物 患者在治疗HIV感染过程中感染的细胞。

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.