To investigate the effects of persistant human immunodeficiency virus (HIV) infection on T cell reactivity, functional properties of peripheral blood T cells from HIV-seropositive homosexual men in various stages of infection were studied. T cell activation via CD3 resulting in proliferation and differentiation was measured in a model system independent of accessory cells, using immobilized anti-CD3 monoclonal antibodies (mAb). T cells from HIV-infected asymptomatic men had a decreased proliferative response compared to HIV-negative controls. T cells from AIDS-related complex (ARC) and AIDS patients, compared to T cells from asymptomatic HIV-infected men, had a significantly lower proliferative response to anti-CD3 mAb. This diminished response to anti-CD3 mAb was shown to be due to decreased interleukin (IL) 2 production and could be enhanced by co-stimulation with anti-CD28 mAb or by adding IL 2. Anti-CD3-induced generation of cytotoxic T lymphocytes was fully intact in early infection but was severely decreased in T cells from ARC and AIDS patients. Cytotoxic activity could be restored to near normal levels after co-stimulation with either anti-CD28 mAb or IL 2. Our data demonstrate a differential loss of T cell functions in the course of HIV infection which is predominantly caused by a lack of IL 2 production after stimulation via the CD3/T cell receptor complex. In early HIV infection this seems to be predominantly caused by a specific loss of memory T cells. However, in later stages of infection when both naive and memory T cell subsets are depleted, resulting in a normal naive/memory T cell ratio, T cell functions further deteriorate probably due to intrinsic activation defects. These findings may be of pathogenic relevance since diminished T cell reactivity may facilitate spreading and replication of virulent HIV variants heralding development of ARC and AIDS.