A Gammaherpesvirus Bcl-2 Ortholog Blocks B Cell Receptor-Mediated Apoptosis and Promotes the Survival of Developing B Cells In Vivo

Coleman, Carrie B.; McGraw, Jennifer E.; Feldman, Emily R.; Roth, Alexa N.; Keyes, Lisa R.; Grau, Katrina R.; Cochran, Stephanie L.; Waldschmidt, Thomas J.; Liang, Chengyu; Forrest, J. Craig; Tibbetts, Scott A.

doi:10.1371/journal.ppat.1003916

Cited by 31 publications

(34 citation statements)

References 107 publications

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“…As found for other gHVs, MHV68 encodes genes that were likely acquired from the host ( Virgin et al, 1997 ) including a viral homolog of the cellular anti-apoptotic bcl-2 protein (vBcl-2, MHV68 M11 ), a homolog of an IL-8 receptor (vGPCR, MHV68 ORF74 ), cyclin D (v-cyclin, MHV68 ORF72 ), and the complement regulatory protein (MHV68 ORF4; Virgin et al, 1997 ). MHV68 M11 exhibits both anti-apoptotic and anti-autophagic functions ( Ku et al, 2008 ; Sinha et al, 2008 ; Xiaofei et al, 2009 ), and functions to promote the survival of infected immature B cells ( Coleman et al, 2014 ). MHV68 expresses the vGPCR (ORF74), a chemokine receptor with homology to human CXCL2, during latency ( Virgin et al, 1997 ; Wakeling et al, 2001 ).…”

Section: Murine Gammaherpesvirus 68 (Mhv68) Infection Of Mice As a Momentioning

confidence: 99%

Interplay of Murine Gammaherpesvirus 68 with NF-kappaB Signaling of the Host

et al. 2016

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Herpesviruses establish a chronic infection in the host characterized by intervals of lytic replication, quiescent latency, and reactivation from latency. Murine gammaherpesvirus 68 (MHV68) naturally infects small rodents and has genetic and biologic parallels with the human gammaherpesviruses (gHVs), Kaposi’s sarcoma-associated herpesvirus and Epstein–Barr virus. The murine gammaherpesvirus model pathogen system provides a platform to apply cutting-edge approaches to dissect the interplay of gammaherpesvirus and host determinants that enable colonization of the host, and that shape the latent or lytic fate of an infected cell. This knowledge is critical for the development of novel therapeutic interventions against the oncogenic gHVs. The nuclear factor kappa B (NF-κB) signaling pathway is well-known for its role in the promotion of inflammation and many aspects of B cell biology. Here, we review key aspects of the virus lifecycle in the host, with an emphasis on the route that the virus takes to gain access to the B cell latency reservoir. We highlight how the murine gammaherpesvirus requires components of the NF-κB signaling pathway to promote replication, latency establishment, and maintenance of latency. These studies emphasize the complexity of gammaherpesvirus interactions with NF-κB signaling components that direct innate and adaptive immune responses of the host. Importantly, multiple facets of NF-κB signaling have been identified that might be targeted to reduce the burden of gammaherpesvirus-associated diseases.

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Section: Murine Gammaherpesvirus 68 (Mhv68) Infection Of Mice As a Momentioning

confidence: 99%

Interplay of Murine Gammaherpesvirus 68 with NF-kappaB Signaling of the Host

et al. 2016

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“…In this study, B cell-specific ATM expression no longer regulated splenic latency during long-term infection. As recently demonstrated by the Tibbetts group, MHV68 infection of developing B cells in the bone marrow is important to support long-term, but not early, viral splenic latency (39). ATM is not depleted in the developing B cells of CD19-Cre-positive ATM c/c mice (40), and this is likely the reason why attenuation of splenic MHV68 latency is limited to early times in this model.…”

Section: Discussionmentioning

confidence: 52%

B Cell-Specific Expression of Ataxia-Telangiectasia Mutated Protein Kinase Promotes Chronic Gammaherpesvirus Infection

Darrah

Kulinski

Mboko

et al. 2017

J Virol

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Manipulation of host cellular pathways is a strategy employed by gammaherpesviruses, including mouse gammaherpesvirus 68 (MHV68), in order to negotiate a chronic infection. Ataxia-telangiectasia mutated (ATM) plays a unique yet incompletely understood role in gammaherpesvirus infection, as it has both proviral and antiviral effects. Chronic gammaherpesvirus infection is poorly controlled in a host with global ATM insufficiency, whether the host is a mouse or a human. In contrast, ATM facilitates replication, reactivation, and latency establishment of several gammaherpesviruses in vitro, suggesting that ATM is proviral in the context of infected cell cultures. The proviral role of ATM is also evident in vivo, as myeloidspecific ATM expression facilitates MHV68 reactivation during the establishment of viral latency. In order to better understand the complex relationship between host ATM and gammaherpesvirus infection, we depleted ATM specifically in B cells, a cell type critical for chronic gammaherpesvirus infection. B cell-specific ATM deficiency attenuated the establishment of viral latency due to compromised differentiation of ATM-deficient B cells. Further, we found that during long-term infection, peritoneal B-1b, but not related B-1a, B cells display the highest frequency of gammaherpesvirus infection. While ATM expression did not affect gammaherpesvirus tropism for B-1 B cells, B cell-specific ATM expression was necessary to support viral reactivation from peritoneal cells during long-term infection. Thus, our study reveals a role of ATM as a host factor that promotes chronic gammaherpesvirus infection of B cells.IMPORTANCE Gammaherpesviruses infect a majority of the human population and are associated with cancer, including B cell lymphomas. ATM is a unique host kinase that has both proviral and antiviral roles in the context of gammaherpesvirus infection. Further, there is insufficient understanding of the interplay of these roles in vivo during chronic infection. In this study, we show that ATM expression by splenic B cells is required for efficient establishment of gammaherpesvirus latency. We also show that ATM expression by peritoneal B cells is required to facilitate viral reactivation during long-term infection. Thus, our study defines a proviral role of B cellspecific ATM expression during chronic gammaherpesvirus infection.KEYWORDS ATM, gammaherpesvirus, B cell, T cell response, reactivation, chronic infection A taxia-telangiectasia (A-T) mutated (ATM) kinase is a multifunctional kinase, insufficiency of which in humans manifests as A-T (1, 2). The function of ATM was originally defined in the context of response to double-stranded DNA breaks. However,

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“…Interestingly, ORF16 of a New World primate rhadinovirus, HVS, and the vBcl-2 gene of a rodent rhadinovirus, MHV-68, could not substitute for KSHV ORF16 and rescue KSHV replication. Moreover, it is known that the MHV-68 vBcl-2 protein exerts important functions in vivo but is not essential for viral replication (52)(53)(54), and unpublished observations indicate that HVS ORF16 is also nonessential (Armin Ensser, personal communication). Apparently, the essential function was acquired more recently in evolution by a common ancestor of RRV and KSHV.…”

Section: Discussionmentioning

confidence: 99%

The Viral Bcl-2 Homologs of Kaposi's Sarcoma-Associated Herpesvirus and Rhesus Rhadinovirus Share an Essential Role for Viral Replication

Lampe

Guenther

Brune

2017

J Virol

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KS-Bcl-2 is a Kaposi's sarcoma-associated herpesvirus (KSHV)-encoded viral Bcl-2 (vBcl-2) homolog which has apoptosis-and autophagy-inhibiting activity when expressed in transfected cells. However, little is known about its function during viral infection. As KS-Bcl-2 is expressed during the lytic replication cycle, we used constitutively lytic and inducibly lytic KSHV mutants to investigate the role of KSBcl-2 during the lytic cycle. We show that KSHV cannot complete the lytic replication cycle and produce infectious progeny in the absence of KS-Bcl-2, indicating that the protein is essential for KSHV replication. Replacement of the KS-Bcl-2 coding sequence, ORF16, by sequences encoding a potent cellular apoptosis and autophagy inhibitor, Bcl-XL, or the cytomegalovirus mitochondrial inhibitor of apoptosis, vMIA, did not rescue KSHV replication, suggesting that KS-Bcl-2 has a function that goes beyond apoptosis and autophagy inhibition. Strikingly, the vBcl-2 proteins of the related ␥ 2 -herpesviruses murine herpesvirus 68 and herpesvirus saimiri did not rescue the replication of a KS-Bcl-2 deletion mutant, but rhesus rhadinovirus (RRV) vBcl-2 did. Deletion of ORF16 from the RRV genome abrogated viral replication, but its replacement by KSHV ORF16 rescued RRV replication, indicating that the essential vBcl-2 function is conserved between these two primate rhadinoviruses. We further show that the KSHV and RRV Bcl-2 homologs localize to the mitochondria and nuclei of infected cells. Deletion of 17 amino acids from the N terminus of KS-Bcl-2 abrogates nuclear localization and KSHV replication, suggesting that KS-Bcl-2 might execute its essential function in the nuclei of infected cells.IMPORTANCE Several viruses express proteins homologous to cellular Bcl-2. Viral Bcl-2 proteins have functions similar to those of cellular Bcl-2: they can inhibit apoptosis, a form of programmed cell death, and autophagy, a self-degradative process for the disposal of dysfunctional or unwanted components. This study shows that the vBcl-2 proteins of KSHV and RRV differ from other vBcl-2 proteins in that they are essential for viral replication. The essential function is separate from the apoptosis-and autophagy-inhibiting activity but correlates with an unusual localization within the cell nucleus, suggesting that these proteins exert a novel function in the nucleus.KEYWORDS KS-Bcl-2, Kaposi's sarcoma-associated herpesvirus, rhesus rhadinovirus, apoptosis, autophagy, vBcl-2, viral replication K aposi's sarcoma-associated herpesvirus (KSHV), also referred to as human herpesvirus 8 (HHV-8), is a ␥ 2 -herpesvirus and the causative agent of Kaposi's sarcoma (KS), primary effusion lymphoma, and multicentric Castleman's disease (1-4).The KSHV life cycle is divided into two distinct phases, latency and lytic replication, which allow the virus to establish a long-term persistent infection. During latency, viral genomes are maintained within the host cell nucleus as circular episomes that are

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A Gammaherpesvirus Bcl-2 Ortholog Blocks B Cell Receptor-Mediated Apoptosis and Promotes the Survival of Developing B Cells In Vivo

Cited by 31 publications

References 107 publications

Interplay of Murine Gammaherpesvirus 68 with NF-kappaB Signaling of the Host

Interplay of Murine Gammaherpesvirus 68 with NF-kappaB Signaling of the Host

B Cell-Specific Expression of Ataxia-Telangiectasia Mutated Protein Kinase Promotes Chronic Gammaherpesvirus Infection

The Viral Bcl-2 Homologs of Kaposi's Sarcoma-Associated Herpesvirus and Rhesus Rhadinovirus Share an Essential Role for Viral Replication

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