Release of human cytomegalovirus from latency by a KAP1/TRIM28 phosphorylation switch

Rauwel, Benjamin; Jang, Suk Min; Cassano, Marco; Kapopoulou, Adamandia; Barde, Isabelle; Trono, Didier

doi:10.7554/elife.06068

Cited by 104 publications

(136 citation statements)

References 63 publications

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“…Also, phosphorylation of KAP1 at S824 has been linked to derepression of lytic genes in CMV-and KSHV-infected cells (32,34). Our results now reveal modulation of KAP1 levels by STAT3 as a mechanism to regulate KSHV lytic susceptibility.…”

Section: Discussionmentioning

confidence: 53%

STAT3 Regulates Lytic Activation of Kaposi's Sarcoma-Associated Herpesvirus

King

Barbachano-Guerrero

et al. 2015

J Virol

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Lytic activation of Kaposi's sarcoma-associated herpesvirus (KSHV) from latency is a critical contributor to pathogenesis and progression of KSHV-mediated disease. Development of targeted treatment strategies and improvement of lytic-phase-directed oncolytic therapies, therefore, hinge on gaining a better understanding of latency-to-lytic-phase transition. A key observation in that regard, also common to other herpesviruses, is the partial permissiveness of latently infected cells to lytic-cycle-inducing agents. Here, we address the molecular basis of why only some KSHV-infected cells respond to lytic stimuli. Since cellular signal transducer and activator of transcription 3 (STAT3) is constitutively active in KSHV-associated cancers, KSHV activates STAT3, and STAT3 has been found to regulate lytic activation of Epstein-Barr virus (EBV)-infected cells, we asked if STAT3 contributes similarly to the life cycle of KSHV. We found that high levels of STAT3 correlate with the refractory state at the single-cell level under conditions of both spontaneous and induced lytic activation; importantly, STAT3 also regulates lytic susceptibility. Further, knockdown of STAT3 suppresses the cellular transcriptional corepressor Krüppel-associated box domain-associated protein 1 (KAP1; also known as TRIM28), and suppression of KAP1 activates lytic genes, including the viral lytic switch RTA, thereby linking STAT3 via KAP1 to regulation of the balance between lytic and latent cells. These findings, taken together with those from EBV-infected and, more recently, herpes simplex virus 1 (HSV-1)-infected cells, cement the contribution of host STAT3 to persistence of herpesviruses and simultaneously reveal an important lead to devise strategies to improve lytic-phasedirected therapies for herpesviruses. IMPORTANCELytic activation of the cancer-causing Kaposi's sarcoma-associated herpesvirus (KSHV) is vital to its life cycle and causation of disease. Like other herpesviruses, however, a substantial fraction of latently infected cells are resistant to lytic-phase-inducing stimuli. Investigating the molecular basis for this refractory state is essential for understanding how the virus persists and how it causes disease and to guide efforts to improve treatment of KSHV-mediated diseases. We found that, like two other herpesviruses, EBV and HSV-1, KSHV exploits the cellular transcription factor STAT3 to regulate the susceptibility of latently infected cells to lytic triggers. These findings highlight a common STAT3-centered strategy used by herpesviruses to maintain persistence in their hosts while also revealing a key molecule to pursue while devising methods to improve herpesvirus lytic-phase-directed therapies.T he oncogenic human gammaherpesvirus human herpesvirus 8 (HHV-8), widely known as Kaposi's sarcoma-associated herpesvirus (KSHV), is the etiologic agent of three human malignancies: Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman's disease (MCD) (1, 2). Like other herpesviruses, KSHV exhi...

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Section: Discussionmentioning

confidence: 53%

STAT3 Regulates Lytic Activation of Kaposi's Sarcoma-Associated Herpesvirus

King

Barbachano-Guerrero

et al. 2015

J Virol

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“…10A). Interestingly, TIF1-beta, which associates with the KRAB domain of zinc finger proteins, has been reported to play a critical role in the latency of another herpesvirus, human cytomegalovirus (91). Several of the DEGs that enriched to the GO term "regulation of cellular processes" (Fig.…”

Section: Fig 7 Immunohistochemistry Gene Validation Ihc Staining Andmentioning

confidence: 99%

Acute Simian Varicella Virus Infection Causes Robust and Sustained Changes in Gene Expression in the Sensory Ganglia

Arnold

Girke

Sureshchandra

et al. 2016

J Virol

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Primary infection with varicella-zoster virus (VZV), a neurotropic alphaherpesvirus, results in varicella. VZV establishes latency in the sensory ganglia and can reactivate later in life to cause herpes zoster. The relationship between VZV and its host during acute infection in the sensory ganglia is not well understood due to limited access to clinical specimens. Intrabronchial inoculation of rhesus macaques with simian varicella virus (SVV) recapitulates the hallmarks of VZV infection in humans. We leveraged this animal model to characterize the host-pathogen interactions in the ganglia during both acute and latent infection by measuring both viral and host transcriptomes on days postinfection (dpi) 3, 7, 10, 14, and 100. SVV DNA and transcripts were detected in sensory ganglia 3 dpi, before the appearance of rash. CD4 and CD8 T cells were also detected in the sensory ganglia 3 dpi. Moreover, lung-resident T cells isolated from the same animals 3 dpi also harbored SVV DNA and transcripts, suggesting that T cells may be responsible for trafficking SVV to the ganglia. Transcriptome sequencing (RNA-Seq) analysis showed that cessation of viral transcription 7 dpi coincides with a robust antiviral innate immune response in the ganglia. Interestingly, a significant number of genes that play a critical role in nervous system development and function remained downregulated into latency. These studies provide novel insights into host-pathogen interactions in the sensory ganglia during acute varicella and demonstrate that SVV infection results in profound and sustained changes in neuronal gene expression. IMPORTANCEMany aspects of VZV infection of sensory ganglia remain poorly understood, due to limited access to human specimens and the fact that VZV is strictly a human virus. Infection of rhesus macaques with simian varicella virus (SVV), a homolog of VZV, provides a robust model of the human disease. Using this model, we show that SVV reaches the ganglia early after infection, most likely by T cells, and that the induction of a robust innate immune response correlates with cessation of virus transcription. We also report significant changes in the expression of genes that play an important role in neuronal function. Importantly, these changes persist long after viral replication ceases. Given the homology between SVV and VZV, and the genetic and physiological similarities between rhesus macaques and humans, our results provide novel insight into the interactions between VZV and its human host and explain some of the neurological consequences of VZV infection. V aricella-zoster virus (VZV) is a neurotropic alphaherpesvirus and the causative agent of varicella (chickenpox) (1). VZV establishes latency in the sensory ganglia and can reactivate later in life to cause herpes zoster (shingles), a painful disease that affects almost 1 million individuals in the United States alone (2). VZV is transmitted through the inhalation of virus-laden saliva droplets or by direct contact with the infectious fluid from vesicles...

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“…HCMV latency in human CD34+ cells depends on the action on the viral genome of KRAB-associated protein 1 (KAP1), a master corepressor, with heterochromatin protein 1 and the SETDB1 histone methyltransferase, which causes transcriptional silencing via heterochromatin-inducing activity. Lytic infection can be induced via the mammalian target of rapamycin pathway or by the activation of the NF-kB pathway with KAP1 phosphorylation and suppression of gene silencing (94). The ability to force CMV out of latency might allow curative therapy for CMV infection in allografts.…”

Section: Viral Genetics and Variability In Immune Responsementioning

confidence: 99%

The Cell Biology of Cytomegalovirus: Implications for Transplantation

Kaminski

Fishman

2016

American Journal of Transplantation

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Interpretation of clinical data regarding the impact of cytomegalovirus (CMV) infection on allograft function is complicated by the diversity of viral strains and substantial variability of cellular receptors and viral gene expression in different tissues. Variation also exists in nonspecific (monocytes and dendritic cells) and specific (NK cells, antibodies) responses that augment T cell antiviral activities. Innate immune signaling pathways and expanded pools of memory NK cells and cd T cells also serve to amplify host responses to infection. The clinical impact of specific memory T cell anti-CMV responses that cross-react with graft antigens and alloantigens is uncertain but appears to contribute to graft injury and to the abrogation of allograft tolerance. These responses are modified by diverse immunosuppressive regimens and by underlying host immune deficits. The impact of CMV infection on the transplant recipient reflects cellular changes and corresponding host responses, the convergence of which has been termed the "indirect effects" of CMV infection. Future studies will clarify interactions between CMV infection and allograft injury and will guide interventions that may enhance clinical outcomes in transplantation.

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Release of human cytomegalovirus from latency by a KAP1/TRIM28 phosphorylation switch

Cited by 104 publications

References 63 publications

STAT3 Regulates Lytic Activation of Kaposi's Sarcoma-Associated Herpesvirus

STAT3 Regulates Lytic Activation of Kaposi's Sarcoma-Associated Herpesvirus

Acute Simian Varicella Virus Infection Causes Robust and Sustained Changes in Gene Expression in the Sensory Ganglia

The Cell Biology of Cytomegalovirus: Implications for Transplantation

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