EXPOSURE OF RESTING PERIPHERAL-BLOOD T-CELLS TO HIV-1 PARTICLES GENERATES CD25(-CELLS IN A SMALL SUBSET, LEADING TO INDUCTION OF APOPTOSIS IN BYSTANDER CELLS() KILLER)

Apoptosis is a major mechanism whereby HIV-1 depletes uninfected CD4() and CD8(+) T cells, We previously showed that resting peripheral blo od T cells derived from healthy donors were killed by an apoptotic mec hanism after adsorption to gp120-containing, protease-defective HIV-1 (L-2) particles, more effectively than parental wild-type LAI adsorpti on or rgp120-mediated CD4 crosslinking, followed by mitogenic stimulat ion, Here, we present evidence that the L-2 particle-based apoptosis w as induced both in CD4(+) and CD8(+) cells by generation of effector c ells which were mainly derived from a resting memory CD4(+)CD38(-) sub set, This subset enhanced the CD25 expression on the surface and secre ted IFN-gamma in the culture supernatant after L-2 particle exposure. Significant elevation of Fas ligand mRNA was found in the subset by L- 2 particle exposure, while expression of Fas antigen on uninfected T c ells was induced by exposure to IFN-gamma. These results indicate that L-2 particles can shift the CD4(+)CD38(-) subpopulation from a restin g to an activated state, and this activation leads to killing of bysta nder CD4(+) and CD8(+) T cells by a Fas-mediated mechanism, In fact, p urified CD4(+)CD38(-) cells exposed to L-2 particles were converted in to effector cells that were able to kill autologous as well as allogen ic target T cells pretreated with IFN-gamma. Further, we found that th e observation of apoptosis due to L-2 particles was a more general phe nomenon, that also occurred with Thai primary HIV-1 isolates, These re sults suggest that such specific types of HIV-1 particles may play a m ajor role in the induction of apoptosis for both bystander CD4(+) and CD8(+) T cells, through inappropriate activation of CD4(+)CD38(-) cell s.