RECONSTRUCTION OF THE THYMUS AFTER HIV INFECTION BY IL-7

尽管有效的抗病毒药物组合的开发保持了 治疗艾滋病毒感染患者前景看好，大多数患者 接受治疗已经破坏了大量的T细胞 淋巴细胞。这些患者过正常生活的能力将 取决于他们身体制造新T淋巴细胞的能力来替代 那些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 不是由艾滋病毒引起的，例如由化疗或辐射引起的 对癌症或骨髓移植患者的治疗表明 胸腺产生新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。 或被艾滋病毒感染损坏，这将进一步降低 以重建成熟的T淋巴细胞室。 因此，恢复胸腺产生新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。vbl.使用 以接受骨髓移植(BMT)的小鼠为模型，我们已经证明 免疫缺陷可以通过给药成功地预防 白介素7的表达。我们还纠正了免疫功能，通过 将IL-7基因导入小鼠骨髓基质细胞。这个 本资助中所述研究的目的是使用IL-7来 在接受抗病毒治疗的患者中刺激新T细胞的发育 艾滋病毒感染的治疗。分离基质细胞的基础研究及临床应用 T细胞，研究将用于开发IL-7治疗计划 恢复HIV感染者的免疫功能。目标1将是 确定正常的人IL-7产生细胞是否像 小鼠为MHCⅡ类+CD45-基质细胞。在Aim 2中，体外 感染艾滋病毒记者将被用来确定是否 产生IL-7的基质细胞是否可感染HIV或HIV 抑制IL-7的产生。在目标3中，载体转导IL-7基因 将被测试为人类基质细胞。目标4中的实验至 确定IL-7是否会导致HIV LTR的反式激活 提供有关可能的毒性的重要临床前信息 HIV感染者血清IL-7水平的变化。这些研究的目标是开发 在未来两年内进行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.