Cystatins are the endogenous inhibitors of cysteine proteases, with cystatin B and cystatin C being the two major inhibitors of cathepsin B. It was believed that cystatin B acted primarily in the intracellular compartment, while cystatin C was actively secreted to act on extracellular cathepsin B. However, recent studies on HIV and other inflammatory diseases have shown high levels of secreted cystatin B in response to either HIV infection or inflammation [43], [49]. This evidence concerns the gene CST4 and HIV infectious disease.