UCSF

CD8(+) cells from healthy HIV-infected individuals can suppress HIV replication in infected CD4(+) cells without killing the cells. This CD8(+) cell noncytotoxic antiviral response (CNAR), observed by coculture of CD8(+) cells with infected CD4(+) cells, is associated with secretion of a CD8(+) cell antiviral factor (CAF). In attempts to identify CAF, we discovered that certain protease inhibitors, particularly leupeptin, can block, by up to 95%, the anti-HIV activity in CD8(+) cell culture fluids as well as inhibit CNAR. The effect is dose-dependent and is observed in up to 70% of the CAF and CNAR assays by using fluids and cells from several different subjects. Pretreatment of CD8(+) cells with leupeptin reduces CNAR, further supporting an inhibitory effect on a CD8(+) cell product. This inhibitory activity of protease inhibitors does not affect cell growth, expression of activation antigens, or viability of either CD8(+) cells or the infected CD4(+) cells. The results suggest that a part of the CD8(+) cell noncytotoxic response involves the activity of a protease or a protein that interacts with protease inhibitors. Proteolysis of a CD8(+) cell product(s) may be involved. This observation offers a promising approach for identifying the mechanism of CNAR/CAF activity.