Clark N M, Hannibal M C, Markovitz D M
Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor 48109-0642, USA.
J Virol. 1995 Aug;69(8):4854-62. doi: 10.1128/JVI.69.8.4854-4862.1995.
Human immunodeficiency virus type 2 (HIV-2), like HIV-1, causes AIDS and is associated with AIDS cases primarily in West Africa. HIV-1 and HIV-2 display significant differences in nucleic acid sequence and in the natural history of clinical disease. Consistent with these differences, we have previously demonstrated that the enhancer/promoter region of HIV-2 functions quite differently from that of HIV-1. Whereas activation of the HIV-1 enhancer following T-cell stimulation is mediated largely through binding of the transcription factor NF-kappa B to two adjacent kappa B sites in the HIV-1 long terminal repeat, activation of the HIV-2 enhancer in monocytes and T cells is dependent on four cis-acting elements: a single kappa B site, two purine-rich binding sites, PuB1 and PuB2, and a pets site. We have now identified a novel cis-acting element within the HIV-2 enhancer, immediately upstream of the kappa B site, designated peri-kappa B. This site is conserved among isolates of HIV-2 and the closely related simian immunodeficiency virus, and transfection assays show this site to mediate HIV-2 enhancer activation following stimulation of monocytic but not T-cell lines. This is the first description of an HIV-2 enhancer element which displays such monocyte specificity, and no comparable enhancer element has been clearly defined for HIV-1. While a nuclear factor(s) from both peripheral blood monocytes and T cells binds the peri-kappa B site, electrophoretic mobility shift assays suggest that either a different protein binds to this site in monocytes versus T cells or that the protein recognizing this enhancer element undergoes differential modification in monocytes and T cells, thus supporting the transfection data. Further, while specific constitutive binding to the peri-kappa B site is seen in monocytes, stimulation with phorbol esters induces additional, specific binding. Understanding the monocyte-specific function of the peri-kappa B factor may ultimately provide insight into the different role monocytes and T cells play in HIV pathogenesis.
2型人类免疫缺陷病毒（HIV-2）与HIV-1一样，会引发艾滋病，主要在西非与艾滋病病例相关联。HIV-1和HIV-2在核酸序列以及临床疾病自然史方面存在显著差异。与这些差异相一致，我们之前已经证明HIV-2的增强子/启动子区域的功能与HIV-1的截然不同。T细胞刺激后HIV-1增强子的激活主要是通过转录因子NF-κB与HIV-1长末端重复序列中两个相邻的κB位点结合来介导的，而单核细胞和T细胞中HIV-2增强子的激活则依赖于四个顺式作用元件：一个单一的κB位点、两个富含嘌呤的结合位点PuB1和PuB2以及一个宠物位点。我们现在在HIV-2增强子内κB位点的紧邻上游鉴定出了一个新的顺式作用元件，命名为κB周边元件。该位点在HIV-2分离株以及密切相关的猴免疫缺陷病毒中是保守的，转染实验表明该位点在单核细胞系而非T细胞系受到刺激后介导HIV-2增强子的激活。这是对显示出这种单核细胞特异性的HIV-2增强子元件的首次描述，并且尚未为HIV-1明确界定出类似的增强子元件。虽然来自外周血单核细胞和T细胞的一种核因子会结合κB周边元件位点，但电泳迁移率变动分析表明，要么是不同的蛋白质在单核细胞与T细胞中结合到该位点，要么是识别该增强子元件的蛋白质在单核细胞和T细胞中经历了差异修饰，从而支持了转染数据。此外，虽然在单核细胞中可以看到与κB周边元件位点的特异性组成性结合，但佛波酯刺激会诱导额外的特异性结合。了解κB周边元件因子的单核细胞特异性功能最终可能会为单核细胞和T细胞在HIV发病机制中所起的不同作用提供深入见解。
