Anergy and apoptosis in CD8⁺ T cells from HIV-infected persons

CD8⁺ T cells from HIV-infected persons increase early in infection, display increased levels of activation Ags, and abnormal MHC-restricted, HIV- specific and nonspecific cytotoxicity abilities. Paradoxically, these cells are also unresponsive to T cell signaling in vitro and have decreased in vitro cloning potential. HIV-specific CTL precursors also are lost late in infection. A quantitative Southern blotting technique showed that CD8⁺ T cells from asymptomatic, HIV-infected persons have increased DNA fragmentation after overnight incubation. DNA fragmentation was reduced by an endonuclease inhibitor but not by cycloheximide, suggesting that a preapoptotic state exists in vivo. Partial inhibition of DNA fragmentation also could be induced by IL-2 addition. No consistent difference in fragmentation was observed among CD8⁺ subpopulations from HIV-infected individuals, although only CD8 T cells that did not express activation Ags (DR^-, CD28⁺, CD57^- phenotype) showed reduced fragmentation when incubated in IL-2. A dramatic increase in CD8⁺, CD28^- cells was observed in asymptomatic HIV-infected people. A subset of CD8⁺, CD28^- cells in both controls and HIV-infected people do not proliferate to T cell signals, and these cells from controls demonstrate increased DNA fragmentation in vitro after 3 days of incubation, regardless of stimulation conditions. This suggests that the cells are end-stage cells. Taken together, the data suggest an increase in anergic or apoptotic CD8⁺ T cells in HIV-infected persons. Eventual depletion of HIV-specific CD8 T cells may occur through a process of proliferation, anergy induction, and apoptosis.