IMMUNOLOGIC APPROACHES TO THE THERAPY OF HIV-1 INFECTION

HIV感染与免疫功能的进行性下降相关，如免疫系统的CD 4 T淋巴细胞库的数量和库的进行性下降所证明的。 该项目的一个主要重点是试图通过使用白细胞介素-2来逆转这一过程，以增加HIV感染背景下的CD 4 T淋巴细胞数量。 在过去一年中，完成了四项第二阶段审判。 这些研究均表明，IL-2能够诱导CD 4 + T细胞计数大幅增加，而HIV水平无重大变化。 此外，对参与IL-2随机对照试验的前157名患者进行的汇总分析表明，CD 4 + T细胞计数长期大幅增加，HIV水平小幅下降，并有减少艾滋病定义疾病的趋势。免疫系统的T细胞分支响应不同抗原的潜力通过T细胞库的多样性来定义。HIV感染不仅导致CD 4 T淋巴细胞总数减少，而且导致T细胞库多样性下降。 为了扩大T细胞库识别和应答HIV感染细胞的能力，利用基因治疗的工具来产生嵌合人T细胞，其不仅表达其天然受体，而且表达对HIV具有特异性的第二受体。 这种方法用于治疗HIV感染患者的可行性是在一项临床试验中建立的，该试验利用了HIV感染不一致的同基因双胞胎对，其中健康双胞胎的细胞被移除，经过遗传修饰以包含对HIV外壳蛋白具有特异性的第二种受体，然后输注到HIV感染的双胞胎中。 虽然这种方法似乎没有任何临床益处，但它确实证明了这样的细胞可以在体内存活，并且当CD 4和CD 8 T细胞都被转移时，与单独转移CD 8 T细胞相反，它们的存活率得到提高。

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.