IMMUNOLOGIC APPROACHES TO THE THERAPY OF HIV 1 INFECTION

这个项目的目的是描述 与艾滋病毒感染相关的免疫异常，发展 HIV患者治疗的免疫学方法 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更多见解 存在于感染艾滋病毒的患者中。艾滋病毒感染与 免疫功能进行性下降，表现为 CD4T的数量和谱系的进行性下降 免疫系统的淋巴细胞池。这一根本性的缺陷 免疫系统是在确定艾滋病毒之前确定的 作为艾滋病的病原体。这个项目的目的是扭转 这一过程是通过使用白细胞介素2(T细胞生长因子)实现的 提高HIV感染者外周血中CD4T淋巴细胞的数量 感染。已经进行了一系列随机研究， 已经确定这是一种可行的增加CD4的方法 对感染艾滋病毒的患者进行计数；这些研究已经 扩展到优化给药方案以最大限度地提高免疫力 病毒学方面的好处，同时将副作用降至最低。一群人 接受这种治疗的患者正在接受跟踪调查 现在超过6年的时期。实验室现在是 参与了一系列与我们外部的合作 美国和国外的同事们，将这一方法扩展到 第三阶段试验。免疫的T细胞分支的潜力 对不同抗原作出反应的系统通过 T细胞谱系的多样性。如上所述，艾滋病毒感染 不仅导致CD4T细胞总数的减少 淋巴细胞，但也导致T细胞的多样性下降 曲目。为了扩大T细胞的能力 识别和应对艾滋病毒感染细胞的曲目，工作是 该项目正在进行中，利用基因治疗的工具来 创造嵌合的人类T细胞，不仅表达他们的天然T细胞 不仅是针对HIV的第二受体，而且是针对HIV的第二个受体。这个 该方法治疗HIV感染者的可行性研究 感染正在使用同基因双胞胎不一致进行检查 对于艾滋病毒感染，即从健康的双胞胎中取出细胞， 基因改造，然后给感染艾滋病毒的双胞胎注射。在……里面 此外，正在进行的研究正在检查DNA的潜力 接种疫苗作为诱导对艾滋病毒的特定免疫力的一种手段。而当 HIV感染会引起抗体的产生，这些抗体 似乎不能对…的过程产生实质性的影响 艾滋病毒感染。随着新知识的产生， 新的HIV包膜蛋白的结构-功能关系 在体内不受免疫系统保护的表位正在被 被确定为抗体治疗的潜在靶点。通过 随机重组文库的生成、抗gp120 现已鉴定出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内开始。 随着新细胞的产生，T细胞池不断发生变化 通过现有细胞的分裂，随着干细胞的分化 通过胸腺环境，随着细胞死亡。在环境中 HIV感染这些变化是由于 与此相关的炎症性和破坏性影响 疾病。为了更好地了解T细胞动力学 在艾滋病毒感染的背景下，有必要获得更好的 了解健康个体的这些过程。一系列 目前正在进行研究，以检查T细胞在体内的周转率 人类利用互补的方法 溴脱氧尿嘧啶核苷和重氢葡萄糖标记 测量单个单元格和池的周转率。

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.