Inhibitors of protein-disulfide isomerase prevent cleavage of disulfide bonds in receptor-bound glycoprotein 120 and prevent HIV-1 entry
Inhibitors of protein-disulfide isomerase prevent cleavage of disulfide bonds in receptor-bound glycoprotein 120 and prevent HIV-1 entry
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DOI：
10.1074/jbc.m204547200
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发表时间：
2002-12-27
影响因子：
4.8
通讯作者：
Ryser, HJP
中科院分区：
文献类型：
--
作者：
Gallina, A;Hanley, TM;Ryser, HJP
我们以前报道过，蛋白质二硫键异构酶（PDI）的单克隆抗体和其他膜不渗透的PDI抑制剂预防HIV-1感染。PDI存在于HIV-1靶细胞的表面，并还原附着于细胞膜的模型肽中的二硫键。在这里，我们表明，可溶性PDI裂解重组包膜糖蛋白gp 120中的二硫键，并结合到表面受体CD 4的gp 120进行二硫键还原，这是防止PDI抑制剂。阻止这种还原并抑制表面结合的二硫键缀合物裂解的抑制剂浓度可在HIV-1进入水平上防止感染。在辅助受体特异性方面不同的HIV-1毒株的进入同样受到抑制，与辅助受体阴性细胞的CD 4结合的gp 120的减少也是如此。PDI抑制剂也阻止HIV-1假型与鼠白血病病毒包膜的融合，但对HIV-1假型的进入没有影响。重要的是，PDI与可溶性和细胞CD 4共沉淀。我们提出，PDI-CD 4协会在细胞表面使PDI达到CD 4结合的病毒，并减少二硫键存在于结合CD 4的gp 120的结构域。由gp 120-二硫环的打开引起的构象变化可能驱动病毒-细胞和细胞-细胞融合的过程。所描述的生物化学事件确定了抗HIV药物的新的潜在靶点。
We previously reported that monoclonal antibodies to protein-disulfide isomerase (PDI) and other membrane-impermeant PDI inhibitors prevented HIV-1 infection. PDI is present at the surface of HIV-1 target cells and reduces disulfide bonds in a model peptide attached to the cell membrane. Here we show that soluble PDI cleaves disulfide bonds in recombinant envelope glycoprotein gp120 and that gp120 bound to the surface receptor CD4 undergoes a disulfide reduction that is prevented by PDI inhibitors. Concentrations of inhibitors that prevent this reduction and inhibit the cleavage of surface-bound disulfide conjugate prevent infection at the level of HIV-1 entry. The entry of HIV-1 strains differing in their coreceptor specificities is similarly inhibited, and so is the reduction of gp120 bound to CD4 of coreceptor-negative cells. PDI inhibitors also prevent HIV envelope-mediated cell-cell fusion but have no effect on the entry of HIV-1 pseudo-typed with murine leukemia virus envelope. Importantly, PDI coprecipitates with both soluble and cellular CD4. We propose that a PDI-CD4 association at the cell surface enables PDI to reach CD4-bound virus and to reduce disulfide bonds present in the domain of gp120 that binds to CD4. Conformational changes resulting from the opening of gp120-disulfide loops may drive the processes of virus-cell and cell-cell fusion. The biochemical events described identify new potential targets for anti-HIV agents.