INDUCTION OF APOPTOSIS BY PROTEASE-DEFECTIVE PARTICLE PREPARATIONS OFHUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 IS SPECIFIC TO A SUBSET OF U937-DERIVED SUBCLONES

Several recent reports support the hypothesis that apoptosis occurring in leukocytes of human immunodeficiency virus type 1 (HIV-1)-infected individuals is important in progression to AIDS. Specifically, apopto sis of uninfected bystander cells appears critical in the pathogenesis of disease. Here, we present evidence that protease-defective, gp120- containing HIV-1 (L-2) particle preparations specifically induce apopt osis in cells obtained from a subset of promonocytic U937-derived subc lones, The rate of apoptosis induction was inversely correlated with t he susceptibility of the U937 subclones to wild-type HIV-1 infection. Three types of apoptosis experiments were performed: DNA content analy sis by flow cytometry, apoptotic nuclear degradation by fluorescent mi croscopy and DNA fragmentation analysis by agarose gel electrophoresis . Kinetic analysis revealed that there was a slower induction of apopt osis by L-2 particle preparations than with tumor necrosis factor (TNF )-alpha or anti-fas antibody. However, there were no significant diffe rences in the initial binding rates of L-2 particles as well as the bi nding of TNF-alpha or anti-fas antibody to the U937 subclones. The bas al level of protein kinase C activity was higher in high-type subclone s compared with low-type subclones. These results suggest that U937 ce lls can be divided into at least two subpopulations, one that permits a productive HIV-1 infection but is not subjected to L-2 particle prep aration-induced apoptosis, while the other poorly replicates HIV-1 and is subjected to L-2 mediated apoptosis, although at a slower rate tha n found with TNF-alpha or anti-fas antibody.