The Mouse Cytomegalovirus Immediate-Early 1 Gene Is Not Required for Establishment of Latency or for Reactivation in the Lungs

Busche, Andreas; Marquardt, Anja; Bleich, André; Ghazal, Peter; Angulo, Ana; Messerle, Martin

doi:10.1128/jvi.02520-08

Cited by 10 publications

(7 citation statements)

References 61 publications

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“…The IE1 protein has long been suspected to be a key player in the events leading to reactivation from hCMV latency although this view has recently been challenged by functional analysis of the mCMV and rCMV IE1 orthologs in mouse and rat models of infection, respectively [37] , [185] . Nonetheless, inflammatory (including allogeneic) immune responses are believed to be efficient stimuli for hCMV reactivation.…”

Section: Discussionmentioning

confidence: 99%

Human Cytomegalovirus IE1 Protein Elicits a Type II Interferon-Like Host Cell Response That Depends on Activated STAT1 but Not Interferon-γ

et al. 2011

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Human cytomegalovirus (hCMV) is a highly prevalent pathogen that, upon primary infection, establishes life-long persistence in all infected individuals. Acute hCMV infections cause a variety of diseases in humans with developmental or acquired immune deficits. In addition, persistent hCMV infection may contribute to various chronic disease conditions even in immunologically normal people. The pathogenesis of hCMV disease has been frequently linked to inflammatory host immune responses triggered by virus-infected cells. Moreover, hCMV infection activates numerous host genes many of which encode pro-inflammatory proteins. However, little is known about the relative contributions of individual viral gene products to these changes in cellular transcription. We systematically analyzed the effects of the hCMV 72-kDa immediate-early 1 (IE1) protein, a major transcriptional activator and antagonist of type I interferon (IFN) signaling, on the human transcriptome. Following expression under conditions closely mimicking the situation during productive infection, IE1 elicits a global type II IFN-like host cell response. This response is dominated by the selective up-regulation of immune stimulatory genes normally controlled by IFN-γ and includes the synthesis and secretion of pro-inflammatory chemokines. IE1-mediated induction of IFN-stimulated genes strictly depends on tyrosine-phosphorylated signal transducer and activator of transcription 1 (STAT1) and correlates with the nuclear accumulation and sequence-specific binding of STAT1 to IFN-γ-responsive promoters. However, neither synthesis nor secretion of IFN-γ or other IFNs seems to be required for the IE1-dependent effects on cellular gene expression. Our results demonstrate that a single hCMV protein can trigger a pro-inflammatory host transcriptional response via an unexpected STAT1-dependent but IFN-independent mechanism and identify IE1 as a candidate determinant of hCMV pathogenicity.

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Section: Discussionmentioning

confidence: 99%

Human Cytomegalovirus IE1 Protein Elicits a Type II Interferon-Like Host Cell Response That Depends on Activated STAT1 but Not Interferon-γ

et al. 2011

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“…In a promonocytic cell-line, ectopic expression of IE1 and IE2 was sufficient for induction of viral early gene expression but not for production of infectious virus [129]. Studies in the mouse and rat models concluded that the IE1 orthologs are not even required for viral reactivation from latency [291][292][293]. Thus, while IE2 is almost certainly necessary for HCMV reactivation (being essential for viral replication) the importance of IE1 in this process remains ambiguous.…”

Section: Role In Viral Replication Latency and Reactivationmentioning

confidence: 99%

Bright and Early: Inhibiting Human Cytomegalovirus by Targeting Major Immediate-Early Gene Expression or Protein Function

Adamson

Nevels

2020

Viruses

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The human cytomegalovirus (HCMV), one of eight human herpesviruses, establishes lifelong latent infections in most people worldwide. Primary or reactivated HCMV infections cause severe disease in immunosuppressed patients and congenital defects in children. There is no vaccine for HCMV, and the currently approved antivirals come with major limitations. Most approved HCMV antivirals target late molecular processes in the viral replication cycle including DNA replication and packaging. “Bright and early” events in HCMV infection have not been exploited for systemic prevention or treatment of disease. Initiation of HCMV replication depends on transcription from the viral major immediate-early (IE) gene. Alternative transcripts produced from this gene give rise to the IE1 and IE2 families of viral proteins, which localize to the host cell nucleus. The IE1 and IE2 proteins are believed to control all subsequent early and late events in HCMV replication, including reactivation from latency, in part by antagonizing intrinsic and innate immune responses. Here we provide an update on the regulation of major IE gene expression and the functions of IE1 and IE2 proteins. We will relate this insight to experimental approaches that target IE gene expression or protein function via molecular gene silencing and editing or small chemical inhibitors.

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“…The difference in the reactivation incidences most likely reflects the difference in the latent viral DNA load (34). As shown recently, although deletion of the regulatory protein IE1 attenuates mCMV (10), an IE1 deletion mutant was still able to reactivate provided that genome loads of WT and mutant virus were adjusted by using higher doses of mutant virus for acute infection (5).…”

mentioning

confidence: 94%

Immune Evasion Proteins Enhance Cytomegalovirus Latency in the Lungs

Böhm

Seckert

Simon

et al. 2009

J Virol

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CD8 T cells control cytomegalovirus (CMV) infection in bone marrow transplantation recipients and persist in latently infected lungs as effector memory cells for continuous sensing of reactivated viral gene expression.Here we have addressed the question of whether viral immunoevasins, glycoproteins that specifically interfere with antigen presentation to CD8 T cells, have an impact on viral latency in the murine model. The data show that deletion of immunoevasin genes in murine CMV accelerates the clearance of productive infection during hematopoietic reconstitution and leads to a reduced latent viral genome load, reduced latency-associated viral transcription, and a lower incidence of recurrence in lung explants.Establishment of latency after clearance of acute infection and the potential to reactivate to recurrent infection are key features of herpesvirus pathogenicity (41). Cytomegaloviruses (CMVs) are usually well controlled by the immune system and cause acute as well as recurrent disease mainly in the immunocompromised or immunologically immature host. Recipients (R) of bone marrow transplantation (BMT) are at risk of reactivating intrinsic human CMV (hCMV) or of becoming infected by reactivating donor (D)-derived hCMV transmitted with the transplant or of both (constellations, respectively) (9). Clinical studies (32, 38) and experimental studies of the murine model of infection with murine CMV (mCMV) (18; reviewed in reference 16) have consistently shown that timely endogenous lymphohematopoietic reconstitution of antiviral CD8 T cells is decisive for coping with CMV infection after BMT. Accordingly, preemptive immunotherapy with antiviral CD8 T cells proved to be a promising approach with the murine model (3,14,35,36,44) and in clinical trials (6,27,40). Both viruses hCMV and mCMV express proteins, so-called immunoevasins, that interfere with the major histocompatibility complex class I pathway of antigen presentation to CD8 T cells (reviewed in reference 33). Whereas many studies have demonstrated the efficacy of immunoevasins in inhibiting the cell surface presentation of antigenic peptides in infected cells in vitro, these molecules do not prevent (11,19,26) but rather enhance (4) the priming of viral epitope-specific CD8 T cells, and their role and relevance in viral pathogenesis in vivo are a currently discussed issue (8). Obviously, research on the in vivo function of immunoevasins by using viral immunoevasin gene deletion mutants can be accomplished only using animal models, and the murine model is well established. Although the detailed molecular modes of action differ between the immunoevasins of hCMV and mCMV, the biological outcome in

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The Mouse Cytomegalovirus Immediate-Early 1 Gene Is Not Required for Establishment of Latency or for Reactivation in the Lungs

Cited by 10 publications

References 61 publications

Human Cytomegalovirus IE1 Protein Elicits a Type II Interferon-Like Host Cell Response That Depends on Activated STAT1 but Not Interferon-γ

Human Cytomegalovirus IE1 Protein Elicits a Type II Interferon-Like Host Cell Response That Depends on Activated STAT1 but Not Interferon-γ

Bright and Early: Inhibiting Human Cytomegalovirus by Targeting Major Immediate-Early Gene Expression or Protein Function

Immune Evasion Proteins Enhance Cytomegalovirus Latency in the Lungs

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