J. Exp. Med., Volume 188, Number 7, October 5, 1998 1255-1265

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

By 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- induced the 16-kD inhibitory C/EBP isoform and coincidentally repressed HIV-1 LTR transcription. C/EBP 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/EBP, but pulmonary tuberculosis abolished inhibitory C/EBP 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/EBP 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.

interferon ;  CCAAT/enhancer binding protein ;  HIV-1 long terminal repeat;  tuberculosis;  repression

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