INHIBITION OF HUMAN-IMMUNODEFICIENCY-VIRUS INFECTION BY AGENTS THAT INTERFERE WITH THIOL-DISULFIDE INTERCHANGE UPON VIRUS-RECEPTOR INTERACTION
INHIBITION OF HUMAN-IMMUNODEFICIENCY-VIRUS INFECTION BY AGENTS THAT INTERFERE WITH THIOL-DISULFIDE INTERCHANGE UPON VIRUS-RECEPTOR INTERACTION
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DOI：
10.1073/pnas.91.10.4559
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发表时间：
1994-05-10
影响因子：
11.1
通讯作者：
DISCIULLO, GJ
中科院分区：
文献类型：
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作者：
RYSER, HJP;LEVY, EM;DISCIULLO, GJ
哺乳动物细胞的细胞表面能够还原性切割外源性膜结合大分子的二硫键（例如，白喉毒素的链间二硫键），并且用膜不渗透性巯基试剂抑制该过程可防止白喉毒素的细胞毒性。最近，人们发现，同样的膜功能可以抑制杆菌肽，蛋白质二硫键异构酶（PDI）的抑制剂，并通过对PDI的单克隆抗体，这表明PDI催化其硫醇和膜结合的大分子的二硫化物之间的硫醇-二硫键交换。我们提供的证据表明，同样的还原过程中发挥了作用，在膜结合的人类免疫缺陷病毒（HIV）的渗透，并表明，HIV感染的人淋巴细胞显着抑制膜不渗透性巯基阻断剂5，5 '-二硫代双（2-硝基苯甲酸），杆菌肽，和抗PDI抗体。结果表明，HIV及其靶细胞参与了由PDI介导的巯基-二硫键交换，并且病毒包膜糖蛋白中关键二硫键的减少可能是引发HIV进入和细胞感染所需的构象变化的初始事件。这些发现表明了阻止HIV感染细胞的其他方法。
The cell surface of mammalian cells is capable of reductively cleaving disulfide bonds of exogenous membrane-bound macromolecules (for instance, the interchain disulfide of diphtheria toxin), and inhibiting this process with membrane-impermeant sulfhydryl reagents prevents diphtheria toxin cytotoxicity. More recently it was found that the same membrane function can be inhibited by bacitracin, an inhibitor of protein disulfide-isomerase (PDI), and by monoclonal antibodies against PDI, suggesting that PDI catalyzes a thiol-disulfide interchange between its thiols and the disulfides of membrane-bound macromolecules. We provide evidence that the same reductive process plays a role in the penetration of membrane-bound human immunodeficiency virus (HIV) and show that HIV infection of human lymphoid cells is markedly inhibited by the membrane-impermeant sulfhydryl blocker 5,5'-dithiobis(2-nitrobenzoic acid), by bacitracin, and by anti-PDI antibodies. The results imply that HIV and its target cell engage in a thiol-disulfide interchange mediated by PDI and that the reduction of critical disulfides in viral envelope glycoproteins may be the initial event that triggers conformational changes required for HIV entry and cell infection. These findings suggest additional approaches to impede cell infection by HIV.