Initiation of a primary immune response requires antigen specific CD4(+) T helper (T(h)) cells to assist in priming of CD8(+) cytotoxic T cell (CTL) activity. This is optimal when T(h) cells and CTL recognize antigen when presented to them by a dendritic cell (DC) in the context of major histocompatibility complex (MHC) class I and class II complexes. We have hypothesized that human DC exposed to HIV-1 gp120 IIIB envelope glycoprotein may activate or alter the immunological activation of DCs. Our findings have led us to conclude that HIV-1 gp120 LAV/IIIB activates monocyte-derived DC when they are in their immature state while HIV-1 gp120 exhibits highly selective effects on mature DC. We have observed that following maturation of DCs with lipopolysaccharide (LPS) that they are less susceptible to the modulatory effects of gp120. Although HIV-1 gp120 activates immature DC, it does so in a manner that abrogates their normal function in host immune responses and consequently disturbs the homeostatic balance of host immune response to infection. We suggest that HIV-1 gp120 may support sustained productive infection and transinfection of activated T cells that cluster with gp120-activated DC. We believe that these are promoted by mechanisms that are dependent, at least in part, on altered cytokine responses, enhanced expression of cellular adhesion molecules and augmented DC-mediated activation of T cells in nonspecific and antigen-specific immune reactivities. Consequently, HIV-1 gp120 may actively contribute to the immunopathogenesis of AIDS.