Differentiation of monocytes to macrophages switches the Mycobacterium tuberculosis effect on HIV-1 replication from stimulation to inhibition: Modulation of interferon response and CCAAT/enhancer binding protein beta expression

HIV-1 replication is inhibited in uninflamed lung macrophages and is stimul ated during tuberculosis, Attempts to recapitulate activation of HIV-1 repl ication in primary monocytes and macrophages ex vivo and in the untreated a nd PMA-treated THP-1 cell line model in vitro have produced opposite result s depending on the state of differentiation of the cells. After infection w ith Mycobacterium tuberculosis, monocytes enhanced HIV-1 replication and pr oduced a stimulatory 37-kDa CCAAT/enhancer binding protein beta (C/EBP beta ) transcription factor, whereas macrophages suppressed HIV-1 replication an d produced an inhibitory 16-kDa C/EBP beta transcription factor. IFN-beta i nduced inhibitory 16-kDa C/EBP beta in macrophages, but had no effect on C/ EBP beta expression in monocytes, Macrophages, but not monocytes, were able to activate IFN-stimulated gene factor-3 (ISGF-3), a transcription factor composed of STAT-1, STAT-2, and IPN regulatory factor (IRF)-9, after infect ion with M. tuberculosis or stimulation with type I IFN, Macrophages expres sed IRF-9 DNA-binding activity, but monocytes did not, and addition of the IRF-9 component reconstituted ISGF-3 in extracts of IFN-treated monocytes, Modulation of IFN responsiveness upon differentiation occurred at least in part through a post-transcriptionally regulated increase in IRF-9 expressio n, Both monocytes and macrophages maintained IFN responsiveness, activating STAT-1 homodimer formation and transcription of the STAT-1 gene after IFN stimulation, In addition, both monocytes and macrophages were able to activ ate NF-kappa B upon infection with M, tuberculosis. These results show that induction of ISGF-3, expression of the inhibitory 16-kDa C/EBP beta, and s uppression of HIV-1 replication via a transcriptional mechanism are macroph age-specific responses to infection with M, tuberculosis.