ANTIHIV T CELL RESPONSES DURING ANTIVIRAL DRUG THERAPY

描述：(改编自申请者摘要)最后一个数字 几个月来，HIV-1感染的临床病程有了显著的改善 在接受联合抗病毒药物治疗的患者中有记录 治疗，包括一种蛋白酶抑制剂和核苷抑制剂。 在多项研究中，大约85%的患者表现出2-3个对数 HIV-1血浆载量下降，CD4T细胞显著增加 人数在没有艾滋病临床治疗至少一年的情况下。 根据依地那韦(默克035)试验的初步结果， 有效的抗病毒治疗一年只能部分恢复 抗HIV-1细胞毒性T淋巴细胞(CTL)免疫对 某些病毒蛋白。T细胞对HIV-1和非HIV-1的识别反应 抗原不是完全重组的。因为T细胞免疫可能是一种 保护HIV-1感染的主要相关因素， 抗逆转录病毒药物治疗可能在一定程度上取决于完全恢复 抗HIV-1 CD8+CTL和CD4+T辅助细胞反应。圆周率假设 这种修复可以通过靶向宿主的治疗来实现 含有某些形式的HIV-1抗原的树突状细胞(DC)将被激活 幼稚的T细胞和扩展记忆的CTL和T辅助细胞 HIV-1-特异性。这项建议的具体目的是：(1)界定 HIV-1特异性CD8+和CD4+T细胞联合治疗前后的反应 治疗，包括艾滋病毒-1表位的描绘、T细胞表型和T细胞 受体谱系；(2)测定DC抗原递送的效果 HIV-1蛋白和基因的体外最佳刺激系统 HIV-1初治受试者的初始CD4+和CD8+T细胞反应；(3)恢复 并增强小鼠体内CD4+T辅助细胞和CD8+CTL对HIV-1的特异性应答 在体外，在HIV-1感染患者中使用基于DC的抗原递送系统 他们在接受治疗后有部分有限的免疫反应 联合抗逆转录病毒药物。

DESCRIPTION: (Adapted From Applicant's Abstract) In the last number of months, dramatic improvements in the clinical course of HIV-1 infection have been documented in patients who are treated with combined antiviral drug therapy and includes a protease inhibitor and nucleoside inhibitors. Approximately 85% of many patients in several studies show a 2-3 log decrease in HIV-1 plasma load, and significant increases in CD4 T-cell numbers in the absence of clinical AIDS for at least one year on therapy. Based on the preliminary results in a trial with Indinavir (Merck 035), potent antiviral therapy for one year results in only partial recovery of anti-HIV-1 cytotoxic T-lymphocyte (CTL) immunity that is selective for certain viral proteins. T-cell recognition responses to HIV-1 and non-HIV-1 antigens are not fully reconstituted. Because T-cell immunity may be a major correlate of protection in HIV-1 infection, the efficacy of antireroviral drug therapy may in part depend on restoration of complete anti-HIV-1 CD8+ CTL and CD4+ T helper cell responses. The PI hypotheses that such restoration can be achieved with therapy by targeting host dendritic cells (DC) with certain forms of HIV-1 antigens that will activate naive T-cells and expand memory CTL and T-helper cells with HIV-1-specificity. The specific aims of this proposal are to: (1) define the HIV-1-specific CD8+ and CD4+ T-cell responses pre- and post-combined therapy, including HIV-1 epitope delineation, T-cell phenotyping and T-cell receptor repertoire; (2) to determine the efficacy of DC-antigen delivery systems for HIV-1 proteins and genes for optimal in vitro stimulation of primary CD4+ and CD8+ T-cell responses in HIV-1-naive subjects; (3) restore and enhance HIV-1-specific responses of CD4+ T helper cells and CD8+ CTL in vitro, using DC-based antigen delivery systems in HIV-1-infected patients who have a partial, limited immunological response after treatment with combined antiretrovirals.