Gamma Interferon Blocks Gammaherpesvirus Reactivation from Latency

Steed, Ashley L.; Barton, Erik S.; Tibbetts, Scott A.; Popkin, Daniel L.; Lutzke, Mary L.; Rochford, Rosemary; Virgin, Herbert W.

doi:10.1128/jvi.80.1.192-200.2006

Cited by 72 publications

(82 citation statements)

References 66 publications

(73 reference statements)

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“…Virus-specific CD8 ϩ T cells are impaired in the production of IFN-␥ (Fig. 4), which is a key mediator of viral control during latency (11,35,52). The virus-specific CD8 ϩ T cells are severely defective in expansion upon secondary antigen encounter (Fig.…”

Section: Discussionmentioning

confidence: 99%

CD80 and CD86 Control Antiviral CD8 ⁺ T-Cell Function and Immune Surveillance of Murine Gammaherpesvirus 68

Fuse¹,

Obar²,

Bellfy³

et al. 2006

J Virol

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The interactions between CD80 and CD86 on antigen-presenting cells and CD28 on T cells serve as an important costimulatory signal in the activation of T cells. Although the simplistic two-signal hypothesis has been challenged in recent years by the identification of different costimulators, this classical pathway has been shown to significantly impact antiviral humoral and cellular immune responses. How the CD80/CD86-CD28 pathway affects the control of chronic or latent infections has been less well characterized. In this study, we investigated its role in antiviral immune responses against murine gammaherpesvirus 68 (MHV-68) and immune surveillance using CD80/CD86 ؊/؊ mice. In the absence of CD80/CD86, primary antiviral CD8 ؉ T-cell responses and the induction of neutralizing antibodies were severely impaired. During long-term immune surveillance, the virus-specific CD8 ؉ T cells were impaired in IFN-␥ production and secondary expansion and exhibited an altered phenotype. Surprisingly, a low level of viral reactivation in the lung was observed, and this effect was independent of CD28 and CTLA-4. Thus, CD80 and CD86, signaling through CD28 and possibly another unidentified receptor, are required for optimal immune surveillance and antiviral immune responses to murine gammaherpesvirus.

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Section: Discussionmentioning

confidence: 99%

CD80 and CD86 Control Antiviral CD8 ⁺ T-Cell Function and Immune Surveillance of Murine Gammaherpesvirus 68

Fuse¹,

Obar²,

Bellfy³

et al. 2006

J Virol

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“…There are several lines of evidence supporting a role for type I IFNs in supporting persistent viral infections. MHV-68 replicates more efficiently from macrophages of IFN-γ receptor-deficient mice and from splenocytes of IFN-α/β receptor-deficient mice (59)(60)(61). IFN-α also promoted the establishment of HSV-1 latency and pseudorabies virus (PRV) in vitro in neurons of the trigeminal ganglion (62).…”

Section: ) (B and C)mentioning

confidence: 99%

Cytoplasmic isoforms of Kaposi sarcoma herpesvirus LANA recruit and antagonize the innate immune DNA sensor cGAS

Zhang

Chan

Samarina

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

134

140

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The latency-associated nuclear antigen (LANA) of Kaposi sarcoma herpesvirus (KSHV) is mainly localized and functions in the nucleus of latently infected cells, playing a pivotal role in the replication and maintenance of latent viral episomal DNA. In addition, N-terminally truncated cytoplasmic isoforms of LANA, resulting from internal translation initiation, have been reported, but their function is unknown. Using coimmunoprecipitation and MS, we found the cGMP-AMP synthase (cGAS), an innate immune DNA sensor, to be a cellular interaction partner of cytoplasmic LANA isoforms. By directly binding to cGAS, LANA, and particularly, a cytoplasmic isoform, inhibit the cGAS-STING-dependent phosphorylation of TBK1 and IRF3 and thereby antagonize the cGASmediated restriction of KSHV lytic replication. We hypothesize that cytoplasmic forms of LANA, whose expression increases during lytic replication, inhibit cGAS to promote the reactivation of the KSHV from latency. This observation points to a novel function of the cytoplasmic isoforms of LANA during lytic replication and extends the function of LANA from its role during latency to the lytic replication cycle.KSHV | cytoplasmic LANA | cyclic GMP-AMP synthase

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“…The proinflammatory cytokine IFN-␥ is critical to control MHV68 reactivation from latency. 40 Although, IFN␥ is not active in the IFN␥R Ϫ/Ϫ mice, its increased presence in …”

Section: Viral Latency and Lung Fibrosis 615mentioning

confidence: 99%

Inhibition of NF-κB Signaling Reduces Virus Load and Gammaherpesvirus-Induced Pulmonary Fibrosis

Krug

Torres-González

Qin

et al. 2010

The American Journal of Pathology

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Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disorder of unknown etiology. Several studies have demonstrated an association between pulmonary infection with a herpesvirus and IPF. Based on those observations, we have developed a mouse model in which interferon (IFN)␥R؊/؊ mice infected intranasally with murine gammaherpesvirus 68 (MHV68) develop lung fibrosis. We hypothesize that viral load was a critical factor for the development of fibrosis. Because nuclear factor (NF)-B signaling is required to efficiently establish gammaherpesvirus, latency we infected IFN␥R Idiopathic pulmonary fibrosis (IPF) is a destructive lung disease of unknown cause, with no proven effective therapy other than lung transplantation.1 Although the cellular and molecular pathways that drive the pathogenesis of IPF are complex and not fully delineated, increasing evidence suggests that a key event in its pathogenesis is ongoing alveolar epithelial injury in association with an abnormal host repair response. Several studies have implicated viral infections as an important factor in IPF pathogenesis. Specifically, Epstein-Barr virus (EBV) DNA and protein have been detected in 40 to 70% of lung tissue of IPF patients, compared with 10 to 17% of lung controls.2-7 Our group has detected viral DNA for EBV, Kaposi's sarcoma-associated herpesvirus (KSHV), and Cytomegalovirus herpesvirus in Ͼ95% of lung samples of IPF patients, with statically higher frequency compared with patients with non-IPF lung diseases. 5 We have developed a model of chronic herpesvirusinduced pulmonary fibrosis infection using the herpesvirus murine gammaherpesvirus 68 (MHV68), a natural pathogen of wild murid rodents that has strong genetic and biological similarities with the human gammaherpesviruses EBV and KSHV. 8 -10 In immunocompetent animals, intranasal infection with MHV68 leads to an acute phase of lytic replication in the lung. Within several weeks, infectious virus is undetectable, and latent virus

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Gamma Interferon Blocks Gammaherpesvirus Reactivation from Latency

Cited by 72 publications

References 66 publications

CD80 and CD86 Control Antiviral CD8 ⁺ T-Cell Function and Immune Surveillance of Murine Gammaherpesvirus 68

CD80 and CD86 Control Antiviral CD8 ⁺ T-Cell Function and Immune Surveillance of Murine Gammaherpesvirus 68

Cytoplasmic isoforms of Kaposi sarcoma herpesvirus LANA recruit and antagonize the innate immune DNA sensor cGAS

Inhibition of NF-κB Signaling Reduces Virus Load and Gammaherpesvirus-Induced Pulmonary Fibrosis

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Gamma Interferon Blocks Gammaherpesvirus Reactivation from Latency

Cited by 72 publications

References 66 publications

CD80 and CD86 Control Antiviral CD8 + T-Cell Function and Immune Surveillance of Murine Gammaherpesvirus 68

CD80 and CD86 Control Antiviral CD8 + T-Cell Function and Immune Surveillance of Murine Gammaherpesvirus 68

Cytoplasmic isoforms of Kaposi sarcoma herpesvirus LANA recruit and antagonize the innate immune DNA sensor cGAS

Inhibition of NF-κB Signaling Reduces Virus Load and Gammaherpesvirus-Induced Pulmonary Fibrosis

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CD80 and CD86 Control Antiviral CD8 ⁺ T-Cell Function and Immune Surveillance of Murine Gammaherpesvirus 68

CD80 and CD86 Control Antiviral CD8 ⁺ T-Cell Function and Immune Surveillance of Murine Gammaherpesvirus 68