Differentiation of Monocytes to Macrophages Switches theMycobacterium tuberculosisEffect on HIV-1 Replication from Stimulation to Inhibition: Modulation of Interferon Response and CCAAT/Enhancer Binding Protein β Expression

Abstract

HIV-1 replication is inhibited in uninflamed lung macrophages and is stimulated during tuberculosis. Attempts to recapitulate activation of HIV-1 replication in primary monocytes and macrophages ex vivo and in the untreated and PMA-treated THP-1 cell line model in vitro have produced opposite results depending on the state of differentiation of the cells. After infection with Mycobacterium tuberculosis, monocytes enhanced HIV-1 replication and produced a stimulatory 37-kDa CCAAT/enhancer binding protein β (C/EBPβ) transcription factor, whereas macrophages suppressed HIV-1 replication and produced an inhibitory 16-kDa C/EBPβ transcription factor. IFN-β induced inhibitory 16-kDa C/EBPβ in macrophages, but had no effect on C/EBPβ 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 IFN regulatory factor (IRF)-9, after infection with M. tuberculosis or stimulation with type I IFN. Macrophages expressed 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 expression. 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 activate NF-κB upon infection with M. tuberculosis. These results show that induction of ISGF-3, expression of the inhibitory 16-kDa C/EBPβ, and suppression of HIV-1 replication via a transcriptional mechanism are macrophage-specific responses to infection with M. tuberculosis.

Infection of Human Macrophages and Dendritic Cells withMycobacterium tuberculosisInduces a Differential Cytokine Gene Expression That Modulates T Cell Response

“…Our results about IFN-␣ production from Mtb-infected MDDC are consistent with the data of Cella et al, who found plasmacytoid DC produce type I IFN in mycobacteria-infected lymph nodes (50). It has been also shown that Mtb infection leads to secretion of type I IFN from THP-1 cells (48). All together these observations indicate that the production of IFN type I could play a dual role in Mtb infection by promoting both Th1 and DC differentiation (51)(52)(53)(54).…”

“…In fact, IFNs were originally identified as cytokines that mediate antiviral immunity, but were also found to mediate a protective role against bacterial infections (48,49). Our results about IFN-␣ production from Mtb-infected MDDC are consistent with the data of Cella et al, who found plasmacytoid DC produce type I IFN in mycobacteria-infected lymph nodes (50).…”

The host type I interferon response to viral and bacterial infections

“…Llike LM, Mtb infects and resides in host macrophages. Infection of various cell types with Mtb has been shown to activate NF-κB and IRF-3, and induce expression of both IFNβ and IFNα [117][118][119][120]. A hypervirulent strain of Mtb that induced higher levels of IFNα than another virulent strain, was shown to kill infected mice at a faster rate [120].…”

Regulation of SIVmac239 Basal Long Terminal Repeat Activity and Viral Replication in Macrophages

“…IFN␤, the predominant type I IFN induced as part of the innate immune response to viral pathogens in the central nervous system (6), has been shown to inhibit HIV/SIV replication in macrophages (7,8), a major source of productive HIV/SIV replication in the brain (5,9). Transcriptional suppression of the HIV/SIV long terminal repeat (LTR) by IFN␤ involves the induction of a truncated, dominant-negative isoform of the transcription factor CCAAT/enhancer-binding protein ␤ (C/EBP␤), LIP (7,10). There are three known isoforms of C/EBP␤ also referred to as NF-IL6 (nuclear factor-IL6) and LAP (liver-enriched transcriptional activation protein), which are alternatively translated from the same mRNA (11,12).…”