Brother M B, Chang H K, Lisziewicz J, Su D, Murty L C, Ensoli B
Howard Hughes Medical Institute, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Virology. 1996 Aug 1;222(1):252-6. doi: 10.1006/viro.1996.0416.
The tat gene product (Tat) of human immunodeficiency virus type 1 (HIV-1) is an early regulatory protein which transactivates HIV-1 gene expression by interacting with the trans-activation response element (TAR) present in the HIV-1 long terminal repeat (LTR). In HIV-1-infected cells Tat can also activate the expression of tumor necrosis factor (TNF). Recent results indicate that essential for this effect is the interaction of Tat with a TAR-like structure present in the TNF beta messenger RNA leader region that closely resembles the TAR of the HIV-LTR. Here we show that because of this similarity of mechanisms, the expression of an RNA species encoding polymeric-TAR sequences and known to inhibit Tat-mediated HIV-1 gene expression also blocks TNF gene expression in response to Tat, but not TNF promoter activation induced by human T cell leukemia/lymphotropic virus type I Tax protein. Since TNF is increased in HIV-1-infected individuals and can activate HIV-1 gene expression or rescue Tat-defective HIV-1 proviruses, activation of TNF by Tat may be part of a complex pathway in which HIV-1 uses its own expression to increase infectivity and to induce disease. This study shows a dual role for the polymeric-TAR construct in inhibiting HIV-1 replication and strengthens the potential use of this protective gene in gene therapy for AIDS.
人类免疫缺陷病毒1型（HIV-1）的tat基因产物（Tat）是一种早期调节蛋白，它通过与HIV-1长末端重复序列（LTR）中存在的反式激活应答元件（TAR）相互作用来反式激活HIV-1基因表达。在HIV-1感染的细胞中，Tat还可激活肿瘤坏死因子（TNF）的表达。最近的结果表明，这种效应的关键在于Tat与TNFβ信使核糖核酸前导区中存在的一种类似TAR的结构相互作用，该结构与HIV-LTR的TAR非常相似。在此我们表明，由于这种机制的相似性，一种编码多聚TAR序列且已知可抑制Tat介导的HIV-1基因表达的RNA种类的表达，也会阻断Tat诱导的TNF基因表达，但不会阻断由人类T细胞白血病/淋巴瘤病毒I型Tax蛋白诱导的TNF启动子激活。由于在HIV-1感染个体中TNF水平升高，且TNF可激活HIV-1基因表达或拯救Tat缺陷的HIV-1前病毒，Tat对TNF的激活可能是一个复杂途径的一部分，在这个途径中，HIV-1利用自身表达来增加感染性并引发疾病。本研究显示了多聚TAR构建体在抑制HIV-1复制中的双重作用，并加强了这种保护性基因在艾滋病基因治疗中的潜在应用。
