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

HeLa细胞对cd4非依赖性HIV感染具有抗性。我们发现胱抑素- c（组织蛋白酶抑制剂）使HeLa细胞易受cd4非依赖性HIV感染。当用低分子量组织蛋白酶抑制剂CA-074Me处理靶细胞时，cd4非依赖性HIV感染增强。由于cd4非依赖性HIV感染被内吞作用抑制剂减弱，感染通过内核体发生。当组织蛋白酶活性相对较高时，由于组织蛋白酶结合到核内体中的HIV颗粒的降解，cd4非依赖性HIV传染性可能降低。虽然小鼠白血病病毒（MLV）感染是通过核内体发生的，但CA-074Me对MLV感染有较强的抑制作用。这一结果表明，与非cd4依赖性HIV感染不同，MLV感染需要组织蛋白酶。由于内核体酸化抑制剂不能抑制XC细胞中的MLV感染，因此人们普遍认为MLV感染不会通过XC细胞中的内核体特异性发生。我们发现，MLV在XC细胞中的感染是通过核内体发生的，而在XC细胞中，组织蛋白酶在没有核内体酸化的情况下激活，使MLV感染对核内体酸化抑制剂具有抗性。

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.