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

HeLa细胞对CD 4非依赖性HIV感染具有抗性。我们确定了胱抑素-C（组织蛋白酶抑制剂），赋予HeLa细胞对CD 4-非依赖性HIV感染易感。当用低分子量组织蛋白酶抑制剂CA-074 Me处理靶细胞时，非CD 4依赖性HIV感染增强。因为CD 4非依赖性HIV感染被内吞抑制剂减弱，所以感染通过内体发生。当组织蛋白酶活性相对较高时，由于组织蛋白酶降解掺入内体的HIV颗粒，CD 4非依赖性HIV感染性可能降低。尽管鼠白血病病毒（MLV）感染通过核内体发生，但MLV感染被CA-074 Me抑制。该结果表明，与CD 4非依赖性HIV感染不同，MLV感染需要组织蛋白酶。由于XC细胞中的MLV感染不受内体酸化抑制剂的抑制，因此广泛认为MLV感染不通过XC细胞中特异性的内体发生。我们发现XC细胞中的MLV感染通过内体发生，并且XC细胞中在没有内体酸化的情况下激活的组织蛋白酶赋予MLV感染对内体酸化抑制剂的抗性。

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.