IMMUNOLOGIC APPROACHES TO THE THERAPY OF HIV 1 INFECTION

该项目的目的是描述 与HIV感染相关的免疫异常， 艾滋病病毒感染者的免疫治疗方法 感染并利用这些基于免疫的疗法作为工具， 获得关于病理生理机制的额外见解 艾滋病病毒感染者中存在。艾滋病毒感染与 随着免疫功能的进行性下降， CD4 T细胞的数量和库进行性下降， 免疫系统的淋巴细胞池。这一基本缺陷， 免疫系统在艾滋病病毒被发现之前就被发现了 作为艾滋病的病原体。该项目旨在扭转 这一过程通过使用白细胞介素-2（T细胞生长因子） 增加HIV感染者的CD4 T淋巴细胞数量 感染已经进行了一系列随机研究， 我已经确定这是一种可行的方法， 艾滋病毒感染者的数量;这些研究已经 扩展以优化最大免疫力的给药方案 和病毒学益处，同时使副作用最小化。队列 接受这种治疗的患者正在接受随访， 现在已经超过6年了。该实验室目前 参与了一系列的合作， 美国和国外的同事，将这种方法扩展到 第三阶段试验。免疫系统T细胞分支的潜力 系统，以响应不同的抗原是通过定义 T细胞库的多样性。如上所述，艾滋病毒感染 不仅导致CD4 T细胞总数减少， 淋巴细胞，而且在T细胞的多样性下降 保留曲目。为了扩大T细胞的能力 剧目识别和应对艾滋病毒感染的细胞，工作是 目前，该项目正在利用基因治疗的工具， 创造出嵌合的人类T细胞， 受体，但也是对HIV具有特异性的第二受体。的 这种方法治疗艾滋病毒感染者的可行性 感染正在检查利用同基因双胞胎对不一致 艾滋病病毒感染，其中健康的双胞胎细胞被删除， 转基因后注入到感染艾滋病毒的双胞胎体内。在 此外，正在进行的研究正在检查DNA的潜力， 接种疫苗作为一种手段，引发对艾滋病毒的特异性免疫力。而 艾滋病毒感染促使抗体的产生，这些抗体 似乎无法对......的进程产生实质性影响 艾滋病毒感染。随着新知识的产生， HIV包膜蛋白的结构-功能关系，新 表位，从体内免疫系统屏蔽，正在被 作为抗体治疗的潜在靶点。通过 随机重组文库的产生，抗gp120 已经鉴定了可能具有治疗价值的抗体。 使用这种抗体的临床试验将在明年开始。 随着新细胞的产生，T细胞库不断发生变化 通过现有细胞的分裂， 通过胸腺环境，随着细胞死亡。背景下 艾滋病毒感染这些变化是由于明显的 与此相关的炎症和破坏性影响 疾病为了更好地了解T细胞在免疫系统中的动态变化， 艾滋病病毒感染的设置，有必要获得更好的 了解健康个体的这些过程。一系列 研究正在进行中，以检查体内T细胞周转率， 人类利用互补的方法， 溴脱氧尿苷和氘代葡萄糖标记能够 测量单个细胞和池的周转率。

The purpose of this project is to characterize the immunologic abnormalities associated with HIV infection, develop immunologic approaches to the therapy of patients with HIV infection and utilize these immune based therapies as tools for obtaining additional insights as to the pathophysiologic mechanisms present in patients with HIV infection. HIV infection is associated with a progressive decline in immune function as evidenced by a progressive decline in the number and the repertoire of the CD4 T lymphocyte pool of the immune system. This fundamental defect in the immune system was identified before the identification of HIV as the etiologic agent of AIDS. This project is aimed at reversing this process through the use of interleukin-2 (T cell growth factor) to increase the number of CD4 T lymphocytes in the setting of HIV infection. A series of randomized studies have been carried out that have established this as a feasible method for increasing the CD4 count in patients with HIV infection; these studies have been extended to optimize the dosing regimens for maximal immunologic and virologic benefit while minimizing side effects. Cohorts of patients are being followed who have received this treatment for periods that now extend beyond 6 years. The laboratory is now engaged in a series of collaborations with our extramural colleagues, both in the US and abroad, to extend this approach to phase III trials. The potential of the T cell limb of the immune system to respond to different antigens is defined through the diversity of the T cell repertoire. As noted above, HIV infection leads not only to a decrease in the total number of CD4 T lymphocytes, but also to a decline in the diversity of the T cell repertoire. In an attempt to expand the ability of the T cell repertoire to recognize and respond to HIV infected cells, work is ongoing under this project to utilize the tools of gene therapy to create chimeric human T cells that express not only their native receptor but also a second receptor with specificity for HIV. The feasibility of this approach for the treatment of patients with HIV infection is being examined utilizing syngeneic twin pairs discordant for HIV infection, in which cells from the healthy twin are removed, genetically modified and then infused to the HIV-infected twin. In addition, studies are underway examining the potential of DNA vaccination as a means of eliciting specific immunity to HIV. While HIV infection elicits the production of antibodies, these antibodies appear incapable of exerting a substantial effect on the course of HIV infection. As new knowledge is derived regarding the structure-function relationships of the HIV envelope protein, new epitopes, shielded from the immune system in vivo, are being identified as potential targets for antibody therapy. Through the generation of random recombinatorial libraries, an anti-gp120 antibody has been identified that may be of therapeutic value. Clinical trials using this antibody will begin within the next year. The T cell pool undergoes constant change as new cells are created through the division of existing cells, as stem cells differentiate through a thymic environment, and as cells die. In the setting of HIV infection these changes are pronounced due to the inflammatory and destructive influences associated with this disease. To gain a better understanding of T cell dynamics in the setting of HIV infection it has been necessary to obtain a better understanding of these processes in healthy individuals. A series of studies are underway to examine rates of T cell turnover in vivo in humans utilizing the complementary approaches of bromodeoxyuridine and deuterated glucose labeling to be able to measure individual cell and pool turnover rates.