Genetic Analyses of Contributions of Viral Interleukin-6 Interactions and Signaling to Human Herpesvirus 8 Productive Replication

Li, Qian; Xiang, Qiwang; Chen, Daming; Nicholas, John

doi:10.1128/jvi.00909-20

Cited by 4 publications

(7 citation statements)

References 50 publications

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“…These results validate that vIL-6REV has equivalent functionality to the wild-type BAC16. Consistent with previous report, vIL-6STOP showed reduced viral gene transcription and encapsurated KSHV virions [ 30 ].…”

Section: Resultssupporting

confidence: 93%

“…To our surprise, vIL-6STOP infection had little impact on the transcriptional landscape of monocytes at 7 dpi, suggesting that sustaining STAT signaling activation may be important for cell reprogramming or vIL-6 is important for KSHV reactivation or maintaining persistent KSHV lytic replication. The phenotype is partly seen in reactivated iSLK cells ([ 30 ] and S5D Fig ). Those two functions of vIL-6 are likely to be mutually exclusive.…”

Section: Resultsmentioning

confidence: 99%

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Virally encoded interleukin-6 facilitates KSHV replication in monocytes and induction of dysfunctional macrophages

Shimoda,

Inagaki,

Davis

et al. 2023

PLoS Pathog

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Kaposi’s sarcoma-associated herpesvirus (KSHV) is an oncogenic double-stranded DNA virus and the etiologic agent of Kaposi’s sarcoma and hyperinflammatory lymphoproliferative disorders. Understanding the mechanism by which KSHV increases the infected cell population is crucial for curing KSHV-associated diseases. Using scRNA-seq, we demonstrate that KSHV preferentially infects CD14+ monocytes, sustains viral lytic replication through the viral interleukin-6 (vIL-6), which activates STAT1 and 3, and induces an inflammatory gene expression program. To study the role of vIL-6 in monocytes upon KSHV infection, we generated recombinant KSHV with premature stop codon (vIL-6(-)) and its revertant viruses (vIL-6(+)). Infection of the recombinant viruses shows that both vIL-6(+) and vIL-6(-) KSHV infection induced indistinguishable host anti-viral response with STAT1 and 3 activations in monocytes; however, vIL-6(+), but not vIL-6(-), KSHV infection promoted the proliferation and differentiation of KSHV-infected monocytes into macrophages. The macrophages derived from vIL-6(+) KSHV infection showed a distinct transcriptional profile of elevated IFN-pathway activation with immune suppression and were compromised in T-cell stimulation function compared to those from vIL-6(-) KSHV infection or uninfected control. Notably, a viral nuclear long noncoding RNA (PAN RNA), which is required for sustaining KSHV gene expression, was substantially reduced in infected primary monocytes upon vIL-6(-) KSHV infection. These results highlight the critical role of vIL-6 in sustaining KSHV transcription in primary monocytes. Our findings also imply a clever strategy in which KSHV utilizes vIL-6 to secure its viral pool by expanding infected monocytes via differentiating into longer-lived dysfunctional macrophages. This mechanism may facilitate KSHV to escape from host immune surveillance and to support a lifelong infection.

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Section: Resultssupporting

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Virally encoded interleukin-6 facilitates KSHV replication in monocytes and induction of dysfunctional macrophages

Shimoda,

Inagaki,

Davis

et al. 2023

PLoS Pathog

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“…Regardless of HIV status, HHV8 is the cause of immune dysregulation in HHV8-MCD. HHV8 replicates in the lymph nodes and leads to the proliferation of viral interleukin-6 (IL-6) 13 14. Viral IL-6 acts similarly to human IL-6 and is proinflammatory, angiogenic and leads to further cytokine release 14.…”

Section: Discussionmentioning

confidence: 99%

“…HHV8 replicates in the lymph nodes and leads to the proliferation of viral interleukin-6 (IL-6) 13 14. Viral IL-6 acts similarly to human IL-6 and is proinflammatory, angiogenic and leads to further cytokine release 14. Histopathology is typically marked by a plasmocytic variant, with hyperplastic germinal centres and sheets of plasma cells in the lymph node interfollicular zone 15.…”

Section: Discussionmentioning

confidence: 99%

HHV-8-associated multicentric Castleman disease with concurrent Kaposi sarcoma

et al. 2022

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Multicentric Castleman disease (MCD) is a rare lymphoproliferative disorder typically manifesting with bulky lymphadenopathy in multiple lymph node stations. We describe an atypical presentation of human herpes virus 8 (HHV8)-associated MCD in a middle-aged man with no significant medical history who presented with 1 month of systemic symptoms. He was found to be HIV-1 positive. A physical examination did not reveal palpable lymphadenopathy. A contrast-enhanced CT scan was notable for hepatosplenomegaly and mildly enlarged scattered lymph nodes in the abdomen and pelvis. A positron emission tomography/CT scan demonstrated hypermetabolic cervical chain lymph nodes. Posterior cervical lymph node pathology showed HHV8-positive MCD with concurrent HIV-associated Kaposi sarcoma. The patient was treated with rituximab and liposomal doxorubicin without response. We emphasise the lack of the hallmark of bulky lymphadenopathy in this patient, and the importance of a timely pathological diagnosis in MCD.

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“…STAT3-dependent expression of survivin is a key mechanism sustaining the viability of latently infected PEL cells [ 25 ]. The mechanism of STAT3 promotion of productive replication in these and other cell types has not been established, but signaling by the virus-encoded IL-6 homologue (vIL-6) through the gp130 cytokine receptor is a major mechanism of STAT3 activation that contributes to productive replication [ 27 , 28 ]. While STAT3 signaling is of demonstrable importance to HHV-8 latent and lytic biology, it seems reasonable to hypothesize that there are mechanisms by which this signaling can be attenuated and fine-tuned to achieve optimal conditions for both phases of infection.…”

Section: Introductionmentioning

confidence: 99%

Direct and biologically significant interactions of human herpesvirus 8 interferon regulatory factor 1 with STAT3 and Janus kinase TYK2

Yang,

Xiang,

Nicholas

2023

PLoS Pathog

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Human herpesvirus 8 (HHV-8) encodes four viral interferon regulatory factors (vIRFs) that target cellular IRFs and/or other innate-immune and stress signaling regulators and suppress the cellular response to viral infection and replication. For vIRF-1, cellular protein targets include IRFs, p53, p53-activating ATM kinase, BH3-only proteins, and antiviral signaling effectors MAVS and STING; vIRF-1 inhibits each, with demonstrated or likely promotion of HHV-8 de novo infection and productive replication. Here, we identify direct interactions of vIRF-1 with STAT3 and STAT-activating Janus kinase TYK2 (the latter reported previously by us to be inhibited by vIRF-1) and suppression by vIRF-1 of cytokine-induced STAT3 activation. Suppression of active, phosphorylated STAT3 (pSTAT3) by vIRF-1 was evident in transfected cells and vIRF-1 ablation in lytically-reactivated recombinant-HHV-8-infected cells led to increased levels of pSTAT3. Using a panel of vIRF-1 deletion variants, regions of vIRF-1 required for interactions with STAT3 and TYK2 were identified, which enabled correlation of STAT3 signaling inhibition by vIRF-1 with TYK2 binding, independently of STAT3 interaction. A viral mutant expressing vIRF-1 deletion-variant Δ198–222 refractory for TYK2 interaction and pSTAT3 suppression was severely compromised for productive replication. Conversely, expression of phosphatase-resistant, protractedly-active STAT3 led to impaired HHV-8 replication. Cells infected with HHV-8 mutants expressing STAT3-refractory vIRF-1 deletion variants or depleted of STAT3 displayed reduced vIRF-1 expression, while custom-peptide-promoted STAT3 interaction could effect increased vIRF-1 expression and enhanced virus replication. Taken together, our data identify vIRF-1 targeting and inhibition of TYK2 as a mechanism of STAT3-signaling suppression and critical for HHV-8 productive replication, the importance of specific pSTAT3 levels for replication, positive roles of STAT3 and vIRF-1-STAT3 interaction in vIRF-1 expression, and significant contributions to lytic replication of STAT3 targeting by vIRF-1.

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Genetic Analyses of Contributions of Viral Interleukin-6 Interactions and Signaling to Human Herpesvirus 8 Productive Replication

Cited by 4 publications

References 50 publications

Virally encoded interleukin-6 facilitates KSHV replication in monocytes and induction of dysfunctional macrophages

Virally encoded interleukin-6 facilitates KSHV replication in monocytes and induction of dysfunctional macrophages

HHV-8-associated multicentric Castleman disease with concurrent Kaposi sarcoma

Direct and biologically significant interactions of human herpesvirus 8 interferon regulatory factor 1 with STAT3 and Janus kinase TYK2

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