Muthumani Karuppiah, Wadsworth Scott A, Dayes Nathanael S, Hwang Daniel S, Choo Andrew Y, Abeysinghe Harindra R, Siekierka John J, Weiner David B
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
AIDS. 2004 Mar 26;18(5):739-48. doi: 10.1097/00002030-200403260-00004.
To analyze a novel compound, which inhibits serine-threonine protein kinase p38, for its possible bioactivity against HIV-1 infection.
Proteins involved in cellular signal transduction pathways represent a novel class of host therapeutic targets for infectious diseases. In this regard the serine/threonine kinase p38 MAPK, a member of the mitogen-activated protein (MAP) kinase superfamily of signal transduction molecules may play an important role in HIV-1 infection. We analyzed the ability of this compound (RWJ67657) to inhibit HIV replication in primary T cells and monocytes. Cellular expression of phospho-p38MAPK was studied by Western blot analysis. Blockade of HIV infection induced apoptosis was measured by Annexin V staining.
p38 inhibitor RWJ67657 was effective in inhibiting HIV-1 replication in both T-cell and monocyte cell lines, irrespective of the coreceptor used by the virus for entry into the cell. Importantly, both reverse transcriptase and protease resistant escape mutant viruses were effectively suppressed by RWJ67657. In addition, the tested compounds block HIV-induced T-cell apoptosis, a critical means of T-cell depletion linked to AIDS progression.
Several steps in the HIV-1 virus life cycle appear to depend on cellular activation, including activation of the p38 pathway. Without activation virus replication is thought to be blocked due to incomplete reverse transcription and a lack of proviral DNA integration. The data collectively illustrate that inhibition of the p38 pathway can affect HIV-1 replication. Interruption of HIV infection by p38 inhibitors underscores the value of exploring antiviral drugs that target host cellular proteins.
分析一种新型化合物，其可抑制丝氨酸 - 苏氨酸蛋白激酶p38，探讨其对HIV - 1感染可能的生物活性。
参与细胞信号转导途径的蛋白质代表了一类新型的传染病宿主治疗靶点。在这方面，丝氨酸/苏氨酸激酶p38 MAPK是丝裂原活化蛋白（MAP）激酶超家族信号转导分子的成员，可能在HIV - 1感染中起重要作用。我们分析了该化合物（RWJ67657）抑制原代T细胞和单核细胞中HIV复制的能力。通过蛋白质印迹分析研究磷酸化p38MAPK的细胞表达。通过膜联蛋白V染色测量HIV感染诱导的细胞凋亡的阻断情况。
p38抑制剂RWJ67657在T细胞和单核细胞系中均能有效抑制HIV - 1复制，无论病毒进入细胞所使用的共受体如何。重要的是，RWJ676⑤⑦能有效抑制逆转录酶和蛋白酶抗性逃逸突变病毒。此外，受试化合物可阻断HIV诱导的T细胞凋亡，这是与艾滋病进展相关的T细胞耗竭的关键途径。
HIV - 1病毒生命周期中的几个步骤似乎依赖于细胞活化，包括p38途径的活化。如果没有活化，病毒复制被认为会因逆转录不完全和缺乏前病毒DNA整合而受阻。这些数据共同表明，抑制p38途径可影响HIV - 1复制。p38抑制剂对HIV感染的阻断突出了探索靶向宿主细胞蛋白的抗病毒药物的价值。
