The immune dysfunction in human immunodeficiency virus (HIV) infection is complex and cannot be explained solely on the basis of numerical depletion of T lymphocytes. Inappropriate, uncontrolled activation of the immune system may be involved. In a test of this hypothesis, five HIV-infected children were prospectively treated with prednisone and selected immunologic and virologic indices were analyzed. Subjects had marked T lymphopenia (CD4+ T lymphocytes < 500 cells/ml) and antigenemia (serum p24 antigen > 30 pg/ml) and were free of opportunistic infections. There was a significant drop in serum p24 antigen concentrations from baseline (60.2 +/- 10.1% SEM; P < 0.005) 4 weeks after initiation of prednisone, which returned to baseline concentrations as the prednisone was tapered. Concomitant with this decrease, there was decreased expression of cell surface activation markers (HLA-DR, CD25 (interleukin 2 receptor) and CD26 (Ta-1)) in peripheral T lymphocytes. There was no significant change in either T lymphocyte subset numbers or mitogen and antigen-specific lymphoproliferation. A regulatory dysfunction of the immune system, allowing inappropriate activation of T lymphocytes, may be involved in the pathogenesis of HIV disease, and further studies involving selective immunosuppression in HIV disease are warranted.