RECONSTRUCTION OF THE THYMUS AFTER HIV INFECTION BY IL-7

尽管有效的抗病毒药物组合的发展 治疗艾滋病毒感染者的巨大希望，大多数患者 接受治疗的人已经有大量的T细胞被破坏， 淋巴细胞 这些病人过正常生活的能力 依赖于他们身体制造新的T淋巴细胞的能力， 被艾滋病毒摧毁的人。 新的T淋巴细胞通常是在 胸腺 然而，对艾滋病毒和获得性免疫缺陷的研究 不是由于艾滋病毒，如化疗或放疗引起的 癌症或骨髓移植患者的治疗，已经表明， 胸腺产生新的T淋巴细胞的能力急剧下降 在青春期。 胸腺微环境也可能受到抑制 或者被艾滋病毒感染所破坏，这将进一步降低 以重建成熟的T淋巴细胞区室。 因此，恢复胸腺产生新的T淋巴细胞的方法 是治愈艾滋病毒感染者战略的重要组成部分。 使用 小鼠接受骨髓移植（BMT）作为模型，我们已经表明， 免疫缺陷可以通过给药成功预防 白细胞介素-（IL-7）。 我们还纠正了免疫功能， 将IL-7基因导入小鼠骨髓基质细胞。 的 本补助金中描述的研究目的是使用IL-7， 刺激接受抗病毒治疗的患者体内新T细胞的发育 治疗HIV感染。 分离的基质细胞的基础研究和 T细胞，研究将用于开发IL-7治疗方案， 恢复HIV感染者的免疫功能。 目标1是 确定是否正常的人IL-7产生细胞，如 小鼠是MHC II类+CD 45-基质细胞。 在目标2中，体外 感染HIV报告基因将用于确定 产生IL-7的基质细胞可被HIV感染或HIV是否 抑制IL-7的产生。 在目的3中，表达IL-7基因的载体 人类基质细胞的实验。 目标4至 确定IL-7是否导致HIV LTR的反式激活， 提供关于可能毒性的重要临床前信息 HIV感染者的IL-7 这些研究的目的是发展 IL-7基因治疗试验

Although the development of effective antiviral drug combinations holds great promise for treatment of HIV-infected patients, most patients receiving therapy have already had destruction of large numbers of T lymphocytes. The ability of these patients to lead normal lives will depend on their body's ability to make new T lymphocytes to replace those destroyed by HIV. New T lymphocytes are normally made in the thymus. However, studies of both HIV and acquired immune deficiencies not due to HIV, such as those caused by chemotherapy or radiation therapy in cancer or bone marrow transplant patients, have shown that the thymus' ability to produce new T lymphocytes decreases dramatically during adolescence. The thymic microenvironment may also be inhibited or damaged by HIV infection, which would further decrease the ability of the thymus to reconstitute the mature T lymphocyte compartment. Therefore, methods to restore the thymic production of new T lymphocytes are a essential part of strategies to cure HIV-infected patients. Using mice receiving bone marrow transplants (BMT) as a model, we have shown that the immune defects can be successfully prevented by administration of interleukin-(IL-7). We have also corrected immune function, by introducing the IL-7 gene into marrow stromal cells of mice. The purpose of the studies described in this grant are to use IL-7 to stimulate the development of new T cells in patients receiving antiviral therapy for HIV infection. Basic studies of isolated stromal cells and T cells, studies will be used to develop an IL-7 treatment program to restore immune function in HIV-infected patients. Aim 1 will be to determine whether the normal human IL-7-producing cell, like that of the mouse is an MHC Class II+ CD45- stromal cell. In Aim 2, in vitro infection with an HIV reporter will be used to determine whether the IL-7 producing stromal cell can be infected by HIV or whether HIV inhibits IL-7 production. In Aim 3, vectors to transduce the IL-7 gene into human stromal cells will be tested. Experiments in Aim 4 to determine whether IL-7 results in transactivation of the HIV LTR will provide important pre-clinical information about possible toxicity of IL-7 in HIV-infected patients. The goal of these studies is to develop an IL-7 gene therapy trial in the next 2 years.