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Yoshihiro Honda^*, Linda Rogers^*, Koh Nakata, Ben-Yang Zhao^||, Richard Pine^||, Yushi Nakai, Katsushi Kurosu^*, William N. Rom^*, and Michael Weiden^*

From the ^* Division of Pulmonary and Critical Care Medicine and Bellevue Chest Service, New York University Medical Center, New York 10016; the Department of Microbiology and Infection, Institute of Medical Science, Tokyo University, Tokyo 108, Japan; the Department of Medicine, Sendai Kosei Hospital, Sendai 980, Japan; and the ^|| Public Health Research Institute, New York 10016

We have previously observed that HIV-1 replication is suppressed in uninflamed lung and increased during tuberculosis. In vitro THP-1 cell–derived macrophages inhibited HIV-1 replication after infection with Mycobacterium tuberculosis. Suppression of HIV-1 replication was associated with inhibition of the HIV-1 long terminal repeat (LTR) and induction of ISGF-3, a type I interferon (IFN)–specific transcription factor. Repression of the HIV-1 LTR required intact CCAAT/enhancer binding protein (C/EBP) sites. THP-1 cell–derived macrophages infected with M. tuberculosis, lipopolysaccharide, or IFN-β induced the 16-kD inhibitory C/EBPβ isoform and coincidentally repressed HIV-1 LTR transcription. C/EBPβ was the predominant C/EBP family member produced in THP-1 macrophages during HIV-1 LTR repression. In vivo, alveolar macrophages from uninflamed lung strongly expressed inhibitory 16-kD C/EBPβ, but pulmonary tuberculosis abolished inhibitory C/EBPβ expression and induced a novel C/EBP DNA binding protein. Therefore, in vitro, proinflammatory stimulation produces an IFN response inhibiting viral replication by induction of a C/EBPβ transcriptional repressor. THP-1 cell–derived macrophages stimulated with type I IFN are similar to alveolar macrophages in the uninflamed lung in vivo. In contrast, the cellular immune response in active pulmonary tuberculosis disrupts this innate immunity, switching C/EBP expression and allowing high level viral replication.

Key Words: interferon β • CCAAT/enhancer binding protein β • HIV-1 long terminal repeat • tuberculosis • repression

Y. Honda's current address is Department of Medicine, Sendai Kosei Hospital, Sendai 980, Japan.

Abbreviations used: BAL, bronchoalveolar lavage; CAT, chloramphenicol acetyltransferase; C/EBP, CCAAT/enhancer binding protein; EMSA, electromobility shift assay; IRF-1, IFN regulatory factor 1; ISGF-3, IFN-stimulated gene factor 3; ISRE, IFN-stimulated response element(s); LAP, liver-activating protein; LIP, liver-enriched inhibitory protein; moi, multiplicity of infection; NF, nuclear factor; NRE, negative regulatory element; Stat, signal transducer and activator of transcription.

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