How does cystatin-C enhance CD4-independent HIV infection?

HeLa细胞对CD4非依赖性HIV感染具有抵抗力。我们发现胱抑素-C(组织蛋白酶抑制物)可使HeLa细胞易受CD4非依赖性HIV感染。当靶细胞被低分子组织蛋白酶抑制剂CA-074Me处理时，CD4非依赖性HIV感染增加。由于CD4非依赖性HIV感染可通过内吞作用抑制剂减弱，因此感染是通过内吞体内发生的。当组织蛋白酶活性相对较高时，由于组织蛋白酶将HIV颗粒降解到内体中，可能会降低非CD4依赖的HIV的感染性。虽然小鼠白血病病毒(MLV)感染是通过内体发生的，但CA-074Me对MLV感染有较强的抑制作用。这一结果表明，组织蛋白酶是MLV感染所必需的，不同于CD4非依赖的HIV感染。由于MLV在XC细胞中的感染不被内体酸化抑制剂抑制，所以人们普遍认为MLV感染不是通过XC细胞中特异的内体发生的。我们发现，MLV在XC细胞中的感染是通过内体发生的，而XC细胞中的组织蛋白酶在没有内体酸化的情况下被激活，从而使MLV感染对内体酸化抑制剂具有抵抗力。

HeLa cells were resistant to CD4-independent HIV infection. We identified cystatin-C (cathepsin protease inhibitor) that conferred HeLa cells susceptible to CD4-independent HIV infection. When target cells were treated with a low molecular weight cathepsin inhibitor, CA-074Me, CD4-independent HIV infection was enhanced. Because CD4-independent HIV infection was attenuated by an endocytosis inhibitor, the infection occurs through endosomes. When cathepsin activity is relatively higher, CD4-independent HIV infectivity may be reduced due to the degradation of HIV particlesincorporated into endosomes by cathepsin. Although murine leukemia virus (MLV) infection occurs via endosomes, MLV infection was rather suppressed by CA-074Me. This result indicates that cathepsin is required for MLV infection unlike CD4-independent HIV infection. Because MLV infection in XC cells is not suppressed by endosome acidificationinhibitors, it is widely accepted that MLV infection does not occur via endosomes specifically in XC cells. We found that MLV infection in XC cells occurs through endosomes, and cathepsin activated without endosome acidification in XC cells confers MLV infection resistant to endosome acidification inhibitors.