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. 2007 Dec 1;179(11):7262-9.
doi: 10.4049/jimmunol.179.11.7262.

CUGBP1 is required for IFNbeta-mediated induction of dominant-negative CEBPbeta and suppression of SIV replication in macrophages

Justyna M Dudaronek  1 , Sheila A Barber, Janice E Clements
Affiliations

CUGBP1 is required for IFNbeta-mediated induction of dominant-negative CEBPbeta and suppression of SIV replication in macrophages

Justyna M Dudaronek et al. J Immunol. .

Abstract

Productive HIV replication in the CNS occurs very early after infection, yet HIV-associated cognitive disorders do not typically manifest until the development of AIDS, suggesting that mechanisms exist in the CNS to control HIV replication and associated virus-induced pathological changes during the acute and asymptomatic stages of disease. Using an established SIV/macaque model of HIV dementia, we recently demonstrated that the mechanisms regulating virus replication in the brain at these stages involve the production of IFNbeta, which induces the truncated, dominant-negative isoform of C/EBPbeta, also referred to as LIP (liver-enriched transcriptional inhibitory protein). Alternative translation of C/EBPbeta mRNA and increased production of LIP can be mediated by CUGBP1 (CUG-repeat RNA-binding protein 1). Because IFNbeta induces the inhibitory C/EBPbeta in macrophages, we considered the possibility that IFNbeta signaling regulates the activity of CUGBP1, resulting in increased expression of LIP and suppression of SIV replication. In this study, we report that IFNbeta induces LIP and suppresses active SIV replication in primary macrophages from rhesus macaques. Further, we demonstrate that IFNbeta induces the phosphorylation of CUGBP1 and the formation of CUGBP1-C/EBPbeta mRNA complexes in the human monocytic U937 cell line. Finally, we demonstrate that CUGBP1 is not only required for IFNbeta-mediated induction of LIP but also for IFNbeta-mediated suppression of SIV replication. These results suggest that CUGBP1 is a previously unrecognized downstream effector of IFNbeta signaling in primary macrophages that likely plays a pivotal role in innate immune responses that control acute HIV/SIV replication in the brain.

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