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CUGBP1 Is Required for IFNβ-Mediated Induction of Dominant-Negative CEBPβ and Suppression of SIV Replication in Macrophages¹

Justyna M. Dudaronek^*, Sheila A. Barber and Janice E. Clements^2,*

^* Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205; and Booz Allen Hamilton, Rockville, MD 20852

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 IFNβ, which induces the truncated, dominant-negative isoform of C/EBPβ, also referred to as LIP (liver-enriched transcriptional inhibitory protein). Alternative translation of C/EBPβ mRNA and increased production of LIP can be mediated by CUGBP1 (CUG-repeat RNA-binding protein 1). Because IFNβ induces the inhibitory C/EBPβ in macrophages, we considered the possibility that IFNβ signaling regulates the activity of CUGBP1, resulting in increased expression of LIP and suppression of SIV replication. In this study, we report that IFNβ induces LIP and suppresses active SIV replication in primary macrophages from rhesus macaques. Further, we demonstrate that IFNβ induces the phosphorylation of CUGBP1 and the formation of CUGBP1-C/EBPβ mRNA complexes in the human monocytic U937 cell line. Finally, we demonstrate that CUGBP1 is not only required for IFNβ-mediated induction of LIP but also for IFNβ-mediated suppression of SIV replication. These results suggest that CUGBP1 is a previously unrecognized downstream effector of IFNβ signaling in primary macrophages that likely plays a pivotal role in innate immune responses that control acute HIV/SIV replication in the brain.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants MH70306, NS47984, and NS07392 (to J.E.C.).

² Address correspondence and reprint requests to Dr. Janice E. Clements, Johns Hopkins School of Medicine, Department of Molecular and Comparative Pathobiology, 733 North Broadway, Building 820, Baltimore, MD 21205. E-mail address: jclement{at}jhmi.edu

³ Abbreviations used in this paper: LTR, long terminal repeat; CUGBP1, CUG-repeat RNA-binding protein 1; LAP, liver-enriched transcriptional activator protein; LIP, liver-enriched transcriptional inhibitory protein; RBP, RNA-binding protein; RIP, ribonucleoprotein immunoprecipitation; RIPA, radioimmunoprecipitation assay; siRNA, small interfering RNA.