HIV-1 replication is markedly upregulated in alveolar macrophages (AM) during pulmonary tuberculosis (TB). This is associated with loss of an inhibitory CCAAT enhancer binding protein , (C/EBP,) transcription factor and activation of nuclear factor (NF)-B. Since the cellular immune response in pulmonary TB requires lymphocyte–macrophage interaction, a model system was developed in which lymphocytes were added to AM. Contact between lymphocytes and AM reduced inhibitory C/EBP,, activated NF-B, and enhanced HIV-1 replication. If contact between lymphocytes and macrophages was prevented, inhibitory C/EBP, expression was maintained and the HIV-1 long terminal repeat (LTR) was not maximally stimulated although NF-B was activated. Antibodies that cross-linked macrophage expressed B-7, and vascular cell adhesion molecule and CD40 were used to mimic lymphocyte contact. All three cross-linking antibodies were required to abolish inhibitory C/EBP, expression. However, the HIV-1 LTR was not maximally stimulated and NF-B was not activated. Maximal HIV-1–LTR stimulation required both lymphocyte-derived soluble factors, and cross-linking of macrophage expressed costimulatory molecules. High level HIV-1–LTR stimulation was also achieved when IL-1,, IL-6, and TNF-, were added to macrophages with cross-linked costimulatory molecules. Contact between activated lymphocytes and macrophages is necessary to down-regulate inhibitory C/EBP,, thereby derepressing the HIV-1 LTR. Lymphocyte-derived cytokines activate NF-B, further enhancing the HIV-1 LTR.
