We have shown that HIV-1 replication is suppressed in uninflamed lung and increased during tuberculosis. In vitro, we recently showed that monocytes increase HIV-1 replication after infection with M. tb. but, surprisingly, we now show M. tb infection inhibits HIV-1 replication in macrophages. Suppression of HIV-1 replication is associated with repression of the HIV-1 LTR and induction of ISGF-3, an interferon- alpha/beta (IFN)-specific transcription-factor complex. Monocytes do not induce ISGF-3 after IFN treatment or infection with M. tb. Intact C/EBP sites in the HIV-1 LTR negative regulatory element (NRE) are required for promoter repression. Macrophages but not monocytes induce an inhibitory 16-kDa C/EBP-Beta isoform coincident with the HIV-1 LTR repression. Low-dose IFN-Beta represses the HIV-1 LTR and induces the 16-kDa inhibitory C/EBP-Beta. During LTR repression, C/EBP-Beta is present in over 95 percent of the NRE/protein complexes. Mouse bone- marrow macrophages deficient in an IFN receptor do not produce the C/EBP-Beta repressor after an inflammatory stimulus. Taken together, these data suggest that, in vitro, proinflammatory stimulation of macrophages produces an antiviral IFN response that induces a C/EBP-Beta transcriptional repressor and inhibits LTR-mediated transcription. In vivo, alveolar macrophages from uninflamed lung are like macrophages treated with IFN-Beta in vitro; both strongly express inhibitory 16-kDa C/EBP-Beta and inhibit HIV-1 replication. Pulmonary tuberculosis abolishes C/EBP-Beta expression and induces a novel C/EBP DNA binding protein in involved lung segments of both HIV-1- infected and immunocompetent patients. Stat-1 homodimer (an IFN-gamma-specific transcription factor) is also induced, but only in immunocompetent tuberculosis patients. A plausible hypothesis for these observations is as follows: In the absence of inflammation, alveolar macrophages are primed by low doses of IFN-Beta. The cellular immune response in pulmonary tuberculosis disrupts this innate immunity, switching C/EBP expression in both HIV-1-infected and immunocompetent patients. The failure to produce IFN-gamma in AIDS patients allows high-level viral replication. This proposal will investigate the regulation of IFN-mediated immunity in uninflamed lung and in tuberculosis. It will also model stimulation of viral replication in tuberculosis and assess how HIV-1 infection alters IFN response. It will investigate the mechanism and effects of inhibitory C/EBP-Beta induction.
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