The Carboxy Terminal Region of the Human Cytomegalovirus Immediate Early 1 (IE1) Protein Disrupts Type II Inteferon Signaling

Bindu Raghavan,Joanne Trgovcich,Charles Cook

doi:10.3390/v6041502

Bindu Raghavan, Joanne Trgovcich + Show 1 more

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https://doi.org/10.3390/v6041502

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Journal: Viruses	Publication Date: Apr 2, 2014
Citations: 63	License type: CC BY 3.0

Affiliation: The Ohio State University

Abstract

Interferons (IFNs) activate the first lines of defense against viruses, and promote innate and adaptive immune responses to viruses. We report that the immediate early 1 (IE1) protein of human cytomegalovirus (HCMV) disrupts signaling by IFNγ. The carboxyl-terminal region of IE1 is required for this function. We found no defect in the initial events in IFNγ signaling or in nuclear accumulation of signal transducer and activator of transcription 1 (STAT1) in IE1-expressing cells. Moreover, we did not observe an association between disruption of IFNγ signaling and nuclear domain 10 (ND10) disruption. However, there is reduced binding of STAT1 homodimers to target gamma activated sequence (GAS) elements in the presence of IE1. Co-immunoprecipitation studies failed to support a direct interaction between IE1 and STAT1, although these studies revealed that the C-terminal region of IE1 was required for interaction with STAT2. Together, these results indicate that IE1 disrupts IFNγ signaling by interfering with signaling events in the nucleus through a novel mechanism.

Highlights

After primary infection, human cytomegalovirus (HCMV) persists for the lifetime of the host, avoiding elimination by the host immune system [1]
The human fibrosarcoma cell line 2C4 was used in a preliminary screen for HCMV cDNA clones that have a role in regulating IFN signaling. 2C4 is a fibrosarcoma cell line engineered to express the T-cell antigen CD2 under the control of the promoter element of the Interferon Induced Transmembrane protein 1 (IFITM1) gene (a.k.a. 9-27, IFI17, CD225) which respond to both type I and II IFNs by increasing cell surface expression of CD2 [34]
We found that the increase in expression of Interferon Response Factor 1 (IRF1) in response to IFNγ is reduced by 52% in immediate early 1 (IE1) expressing cells as compared to cells nucleofected with empty vector (Figure 1B) relative to untreated cells

Summary

Introduction

Human cytomegalovirus (HCMV) persists for the lifetime of the host, avoiding elimination by the host immune system [1]. In congenitally infected infants and immunosuppressed persons, HCMV can cause serious diseases [2]. Aspects of both HCMV disease and persistence in human populations are suspected to be linked to the multiple mechanisms this virus has evolved to modulate human immune responses. Interferons direct intrinsic cellular defenses and early immune responses against HCMV and other viruses. IFNs function to limit virus replication and pathogenesis through stimulation of intrinsic cellular defense mechanisms that contribute to innate immunity [4,5], and by promoting and regulating adaptive immune responses [6,7]

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