IL-12 production in HIV-infected (HIV + ) individuals is severely impaired after stimulation by bacterial products or T cell-dependent stimuli. Because CD40-CD40 ligand (CD40L) interactions are the major mechanism involved in the T cell-dependent activation of antigenpresenting cells, we investigated whether this pathway was functional in HIV + donors. CD40 expression was increased on freshly isolated monocytes from HIV + individuals compared to HIV -donors. However, equivalent CD40 expression was obtained in the two groups after cytokine stimulation. Since CD40 expression was intact in HIV + donors' cells, we determined whether IL-12 production could be restored by providing exogenous T cell-dependent stimuli, CD40L and IFN-+ , at the time of bacterial stimulation. IL-12 production was not altered by CD40L alone, was increased by IFN-+ , and was synergistically restored to normal values by IFN-+ + CD40L. This combination was more efficient for enhancing IL-12 production than granulocyte-macrophage colony-stimulating factor + CD40L or neutralizing anti-IL-10 antibody + CD40L. CD40L did not affect IL-10 production, whereas IFN-+ significantly decreased it. This study demonstrates that the defect in IL-12 production by leukocytes from HIV + donors can be overcome in vitro if the interacting cells are provided with the right T celldependent co-stimuli.