Luznik L, Kraus G, Guatelli J, Richman D, Wong-Staal F
Department of Medicine, University of California, School of Medicine, San Diego 92093.
J Clin Invest. 1995 Jan;95(1):328-32. doi: 10.1172/JCI117660.
The replication of human immunodeficiency retroviruses involves a complex series of events that is regulated at both transcriptional and posttranscriptional levels. The tat gene product is a potent trans-activator of viral transcription and therefore an attractive target for the development of antiviral drugs. Tat-defective HIV-1 proviral DNA clones have been shown previously to be replication defective. In this study, we report that tat-defective HIV-1 and HIV-2 viral DNA transfected into U937 cells can direct efficient viral replication in the presence of transcriptional stimulators such as TNF-alpha and PMA. In MT-4 cells, tat-defective HIV-1 can replicate without any stimulation. The viruses recovered from MT-4 cells remained tat defective defined by their inability to infect T cell lines (e.g., Molt 4/8) although replication could be rescued with cytokines. Limited replication was observed in primary mononuclear cells. Furthermore, we showed that Ro 24-7429, a potent tat antagonist and antiviral compound, failed to suppress HIV-1 replication in TNF-alpha-stimulated T cells. These results have important implications for targeting tat as a therapeutic strategy for AIDS.
人类免疫缺陷逆转录病毒的复制涉及一系列复杂的事件，这些事件在转录和转录后水平均受到调控。Tat基因产物是病毒转录的有效反式激活因子，因此是开发抗病毒药物的一个有吸引力的靶点。先前已证明Tat缺陷型HIV-1前病毒DNA克隆复制存在缺陷。在本研究中，我们报告转染到U937细胞中的Tat缺陷型HIV-1和HIV-2病毒DNA在存在转录刺激因子如TNF-α和PMA的情况下能够指导有效的病毒复制。在MT-4细胞中，Tat缺陷型HIV-1无需任何刺激即可复制。从MT-4细胞中回收的病毒仍然Tat缺陷，这是由它们无法感染T细胞系（如Molt 4/8）所定义的，尽管细胞因子可以挽救其复制。在原代单核细胞中观察到有限的复制。此外，我们表明Ro 24-7429，一种有效的Tat拮抗剂和抗病毒化合物，未能抑制TNF-α刺激的T细胞中的HIV-1复制。这些结果对于将Tat作为艾滋病治疗策略的靶点具有重要意义。
