IMMUNOLOGIC APPROACHES TO THE THERAPY OF HIV-1 INFECTION

HIV感染与免疫功能的进行性下降有关，免疫系统的CD4T淋巴细胞池的数量和谱系的进行性下降就是明证。该项目的一个主要焦点是试图通过使用白细胞介素2来逆转这一过程，以增加艾滋病毒感染环境中CD4T淋巴细胞的数量。在过去的一年里，已经完成了四项第二阶段试验。其中每一项都证明了IL-2能够诱导CD4+T细胞数量的大幅增加，而不会对艾滋病毒水平产生重大影响。此外，对参加IL-2随机对照试验的前157名患者进行的综合分析表明，CD4+T细胞计数长期大幅增加，艾滋病毒水平略有下降，定义为艾滋病的疾病有减少的趋势。免疫系统的T细胞分支对不同抗原的反应能力是通过T细胞谱系的多样性来确定的。HIV感染不仅导致CD4T淋巴细胞总数的减少，而且还导致T细胞库的多样性下降。为了扩大T细胞识别和应答HIV感染细胞的能力，利用基因治疗工具创造了嵌合的人类T细胞，不仅表达它们的天然受体，而且还表达对HIV具有特异性的第二受体。这种治疗艾滋病毒感染患者的方法的可行性是在一项临床试验中确定的，该试验使用了针对艾滋病毒感染的不协调的同基因双胞胎对，其中来自健康双胞胎的细胞被移除，经过基因修改以包括第二个对艾滋病毒外壳蛋白具有特异性的受体，然后将其注入感染艾滋病毒的双胞胎。虽然这种方法似乎没有任何临床上的好处，但它确实证明了这些细胞可以在体内存活，并且当同时转移CD4和CD8T细胞时，它们的存活率提高了，而不是只转移CD8T细胞。

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. A major focus of this project is attempting to reverse this process through the use of interleukin-2 to increase the number of CD4 T lymphocytes in the setting of HIV infection. Over the past year, four phase II trials have been completed. Each of these has demonstrated that IL-2 is capable of inducing a substantial increase in CD4+ T cell count without major changes in levels of HIV. In addition, a pooled analysis of the first 157 patients enrolled in randomized, controlled trials of IL-2 have demonstrated long term substantial increases in CD4+ T cell counts, small decreases in levels of HIV and a trend towards fewer AIDS-defining illnesses. 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. 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, the tools of gene therapy were utilized 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 was established in a clinical trial utilizing syngeneic twin pairs discordant for HIV infection, in which cells from the healthy twin were removed, genetically modified to include a second receptor with specificity for the coat protein of HIV and then infused to the HIV-infected twin. While there did not appear to be any clinical benefit to this approach it did demonstrate that such cells could survive in vivo and that their survival was enhanced when both CD4 and CD8 T cells were transferred as opposed to the transfer of CD8 T cells alone.