Lisziewicz J, Sun D, Lisziewicz A, Gallo R C
Laboratory of Tumor Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4255, USA.
Gene Ther. 1995 May;2(3):218-22.
Antitat is an autoregulated gene expressing an inhibitory RNA with dual function: it sequesters the Tat protein by polymeric-TAR and blocks the translation of the Tat messenger RNA by antisense-Tat. Using human T cell lines and peripheral blood lymphocytes as the in vitro target, we have previously shown that antitat is an effective long-term suppressor of HIV-1, including 'field' isolates. To assess the efficacy of this inhibitory gene better in the setting of an infected individual with late-stage AIDS, we examined its antiviral activity in an in vivo established infection. Peripheral blood mononuclear cells isolated from AIDS patients were transduced with replication defective retroviral vectors carrying the antitat gene. In the absence of cell selection, the antitat gene blocked virus replication and allowed infected CD4+ T cells to expand in culture. These results suggest that antitat gene therapy may be beneficial to block HIV-1 replication and reconstitute the immune system of late-phase AIDS patients. We introduced a new parameter, CRF, which defines the effectiveness of the ex vivo gene therapy treatment of AIDS patients. Antitat treatment was efficient in cells of all patients regardless of viral quasispecies, however, it was most potent in severely immunocompromised individuals.
反式作用因子抑制基因（Antitat）是一种可自我调节的基因，表达具有双重功能的抑制性RNA：它通过多聚TAR序列隔离反式激活因子（Tat）蛋白，并通过反义Tat序列阻断Tat信使RNA的翻译。我们之前使用人类T细胞系和外周血淋巴细胞作为体外靶点，证明了Antitat是HIV-1的一种有效的长期抑制剂，包括“野生型”分离株。为了在晚期艾滋病感染个体中更好地评估这种抑制基因的疗效，我们在体内已建立的感染模型中检测了其抗病毒活性。从艾滋病患者中分离出的外周血单核细胞用携带Antitat基因的复制缺陷型逆转录病毒载体进行转导。在没有细胞筛选的情况下，Antitat基因阻断了病毒复制，并使受感染的CD4+ T细胞在培养中得以扩增。这些结果表明，Antitat基因治疗可能有助于阻断HIV-1复制并重建晚期艾滋病患者的免疫系统。我们引入了一个新参数，即CRF，它定义了艾滋病患者体外基因治疗的有效性。无论病毒准种如何，Antitat治疗对所有患者的细胞都有效，然而，它在严重免疫受损个体中最为有效。
