INTERLEUKIN-2 INDUCES CD8(+) T-CELL-MEDIATED SUPPRESSION OF HUMAN-IMMUNODEFICIENCY-VIRUS REPLICATION IN CD4(+) T-CELLS AND THIS EFFECT OVERRIDES ITS ABILITY TO STIMULATE VIRUS EXPRESSION

The nonlytic suppression of human immunodeficiency virus (HIV) production from infected CD4(+) T cells by CD8(+) lymphocytes from HIV-infected individuals is one of the most potent host-mediated antiviral activities observed in vitro. We demonstrate that the pleiotropic cytokine interleukin 2 (IL-2), but not IL-12, is a potent inducer of the CD8(+) HIV suppressor phenomenon. IL-2 induces HIV expression in peripheral blood or lymph node mononuclear cells from HIV-infected individuals in the absence of CD8(+) T cells. However, IL-2 induces CD8(+) T cells to suppress HIV expression when added back to these cultures, and this effect dramatically supersedes the ability of IL-2 to induce HIV expression. Five to 25 times fewer CD8(+) cells were required to obtain comparable levels of inhibition of viral production if they were activated in the presence of IL-2 as compared with IL-12 or no exogenous cytokine. Furthermore, IL-2 appeared either to induce a qualitative increase in HIV suppressor cell activity or to increase the relative frequency of suppressor cells in the activated (CD25(+)) CD8(+) populations. Analyses of proviral levels in peripheral blood mononuclear cells suggest that CD8(+) T cell-mediated lysis of in vivo infected cells is not induced by IL-2. These results have implications for our understanding of the effects of impaired IL-2 production during HIV disease as well as the overall effects of IL-2-based immunotherapy on HIV replication in vivo.