The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1998/10/1255/ $5.00
The Journal of Experimental Medicine, Volume 188, Number 7, October 5, 1998 1255-1265


Articles

Type I Interferon Induces Inhibitory 16-kD CCAAT/ Enhancer Binding Protein (C/EBP)β, Repressing the HIV-1 Long Terminal Repeat in Macrophages: Pulmonary Tuberculosis Alters C/EBP Expression, Enhancing HIV-1 Replication

Yoshihiro Honda*, Linda Rogers*, Koh Nakata{ddagger}, 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 {ddagger} 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


Address correspondence to Michael Weiden, Division of Pulmonary and Critical Care Medicine and Bellevue Chest Service, NYU Medical Center, 550 First Ave., New York, NY 10016. Phone: 212-263-7889; Fax: 212-263-8501; E-mail: weidem01{at}gcrc.med.nyu.edu

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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