scholarly journals Deletion of Murine Gammaherpesvirus Gene M2 in Activation-Induced Cytidine Deaminase-Expressing B Cells Impairs Host Colonization and Viral Reactivation

2020 ◽  
Vol 95 (1) ◽  
Author(s):  
Shana M. Owens ◽  
Darby G. Oldenburg ◽  
Douglas W. White ◽  
J. Craig Forrest
Keyword(s):  
Immune System ◽  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
Viral Reactivation ◽  
Viral Gene ◽  
Gene Products ◽  
Chronic Infections ◽  
Murine Gammaherpesvirus

ABSTRACT Gammaherpesviruses (GHVs) are DNA tumor viruses that establish lifelong, chronic infections in lymphocytes of humans and other mammals. GHV infections are associated with numerous cancers, especially in immunocompromised hosts. While it is known that GHVs utilize host germinal center (GC) B cell responses during latency establishment, an understanding of how viral gene products function in specific B cell subsets to regulate this process is incomplete. Using murine gammaherpesvirus 68 (MHV68) as a small-animal model to define mechanisms of GHV pathogenesis in vivo, we generated a virus in which the M2 gene was flanked by loxP sites (M2.loxP), enabling the use of Cre-lox technology to define M2 function in specific cell types in infection and disease. The M2 gene encodes a protein that is highly expressed in GC B cells that promotes plasma cell differentiation and viral reactivation. M2 was efficiently deleted in Cre-expressing cells, and the presence of loxP sites flanking M2 did not alter viral replication or latency in mice that do not express Cre. In contrast, M2.loxP MHV68 exhibited a deficit in latency establishment and reactivation that resembled M2-null virus, following intranasal (IN) infection of mice that express Cre in all B cells (CD19-Cre). Nearly identical phenotypes were observed for M2.loxP MHV68 in mice that express Cre in germinal center (GC) B cells (AID-Cre). However, colonization of neither draining lymph nodes after IN infection nor the spleen after intraperitoneal (IP) infection required M2, although the reactivation defect was retained. Together, these data confirm that M2 function is B cell-specific and demonstrate that M2 primarily functions in AID-expressing cells to facilitate MHV68 dissemination to distal latency reservoirs within the host and reactivation from latency. Our study reveals that a viral latency gene functions within a distinct subset of cells to facilitate host colonization. IMPORTANCE Gammaherpesviruses establish lifelong chronic infections in cells of the immune system that can lead to lymphomas and other diseases. To facilitate colonization of a host, gammaherpesviruses encode gene products that manipulate processes involved in cellular proliferation and differentiation. Whether and how these viral gene products function in specific cells of the immune system is poorly defined. We report here the use of a viral genetic system that allows for deletion of specific viral genes in discrete populations of cells. We employ this system in an in vivo model to demonstrate cell-type-specific requirements for a particular viral gene. Our findings reveal that a viral gene product can function in distinct cellular subsets to direct gammaherpesvirus pathogenesis.

scholarly journals Deletion of Murine Gammaherpesvirus Gene M2 in AID-Expressing B Cells Impairs Host Colonization and Viral Reactivation

2020 ◽  
Author(s):  
Shana M. Owens ◽  
Darby G. Oldenburg ◽  
Douglas W. White ◽  
J. Craig Forrest
Keyword(s):  
Immune System ◽  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
Viral Reactivation ◽  
Viral Gene ◽  
Gene Products ◽  
Chronic Infections ◽  
Murine Gammaherpesvirus

ABSTRACTGammaherpesviruses (GHVs) are DNA tumor viruses that establish life-long, chronic infections in lymphocytes of humans and other mammals. GHV infections are associated with numerous cancers, especially in immune compromised hosts. While it is known that GHVs utilize host germinal center (GC) B cell responses during latency establishment, an understanding of how viral gene products function in specific B cell subsets to regulate this process is incomplete. Using murine gammaherpesvirus 68 (MHV68) as a small-animal model to define mechanisms of GHV pathogenesis in vivo, we generated a virus in which the M2 gene was flanked by loxP sites (M2.loxP), enabling the use of Cre-lox technology to define M2 function in specific cell types in infection and disease. The M2 gene encodes a protein that is highly expressed in GC B cells that promotes plasma cell differentiation and viral reactivation. M2 was efficiently deleted in Cre-expressing cells, and the presence of loxP sites flanking M2 did not alter viral replication or latency in mice that do not express Cre. In contrast, M2.loxP MHV68 exhibited a deficit in latency establishment and reactivation that resembled M2-null virus, following intranasal (IN) infection of mice that express Cre in all B cells (CD19-Cre). Nearly identical phenotypes were observed for M2.loxP MHV68 in mice that express Cre in germinal center (GC) B cells (AID-Cre). However, neither colonization of draining lymph nodes after IN infection nor the spleen after intraperitoneal (IP) infection required M2, although the reactivation defect was retained. Together, these data confirm that M2 function is B cell-specific and demonstrate that M2 primarily functions in AID-expressing cells to facilitate MHV68 dissemination to distal latency reservoirs within the host and reactivation from latency. Our study reveals that a viral latency gene functions within a distinct subset of cells to facilitate host colonization.IMPORTANCEGammaherpesviruses establish life-long chronic infections in cells of the immune system that can lead to lymphomas and other diseases. To facilitate colonization of a host, gammaherpesviruses encode gene products that manipulate processes involved in cellular proliferation and differentiation. Whether and how these viral gene products function in specific cells of the immune system is poorly defined. We report here the use of a viral genetic system that allows for deletion of specific viral genes in discrete populations of cells. We employ this system in an in vivo model to demonstrate cell-type-specific requirements for a particular viral gene. Our findings reveal that a viral gene product can function in distinct cellular subsets to direct gammaherpesvirus pathogenesis.

scholarly journals Telomerase activation in normal B lymphocytes and non-Hodgkin's lymphomas

Blood ◽  
1996 ◽  
Vol 88 (1) ◽  
pp. 222-229 ◽  
Author(s):  
KF Norrback ◽  
K Dahlenborg ◽  
R Carlsson ◽  
G Roos
Keyword(s):  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
Telomerase Activity ◽  
Lymphoid Tissues ◽  
Low Grade ◽  
Malignant Lymphomas ◽  
Hodgkin's Lymphomas ◽  
Germinal Center B Cells

Abstract Activation of telomerase seems to be a prerequisite for immortalization and is found in permanent cell lines and most malignant tumors. Normal somatic cells are generally telomerase negative, except for bone marrow stem cells. Weak activity is also present in peripheral blood cells. In the present study strong telomerase activity was demonstrated in vivo in normal mature cells of the immune system, as well as in malignant lymphomas. Benign lymph nodes had lower telomerase activity than benign tonsils, which exhibited intermediate to high activity comparable with findings in malignant lymphomas. In benign tonsils the activity seemed to be restricted to germinal center B cells. In benign lymphoid tissues telomerase activity correlated with B-cell numbers and cell proliferation, but this was not observed in the lymphoma group. High- grade lymphomas exhibited higher levels of telomerase compared with low- grade cases. The data showed that in vivo activation of telomerase is a characteristic feature of germinal center B cells. Different signals for activation of telomerase are likely to exist, one of them being immune stimulation. The data suggest that telomerase activity in malignant lymphomas can be explained by an “induction and retention” model, ie, transformation occurs in a normal, mature B cell with reactivated telomerase, which is retained in the neoplastic clone.

scholarly journals Mouse model of Epstein–Barr virus LMP1- and LMP2A-driven germinal center B-cell lymphoproliferative disease

2017 ◽  
Vol 114 (18) ◽  
pp. 4751-4756 ◽  
Author(s):  
Takeharu Minamitani ◽  
Yijie Ma ◽  
Hufeng Zhou ◽  
Hiroshi Kida ◽  
Chao-Yuan Tsai ◽  
...  
Keyword(s):  
B Cells ◽  
Mouse Model ◽  
B Cell ◽  
Germinal Center ◽  
Epstein Barr Virus ◽  
Target Genes ◽  
Nk Cell ◽  
Barr Virus ◽  
Epstein Barr

Epstein–Barr virus (EBV) is a major cause of immunosuppression-related B-cell lymphomas and Hodgkin lymphoma (HL). In these malignancies, EBV latent membrane protein 1 (LMP1) and LMP2A provide infected B cells with surrogate CD40 and B-cell receptor growth and survival signals. To gain insights into their synergistic in vivo roles in germinal center (GC) B cells, from which most EBV-driven lymphomas arise, we generated a mouse model with conditional GC B-cell LMP1 and LMP2A coexpression. LMP1 and LMP2A had limited effects in immunocompetent mice. However, upon T- and NK-cell depletion, LMP1/2A caused massive plasmablast outgrowth, organ damage, and death. RNA-sequencing analyses identified EBV oncoprotein effects on GC B-cell target genes, including up-regulation of multiple proinflammatory chemokines and master regulators of plasma cell differentiation. LMP1/2A coexpression also up-regulated key HL markers, including CD30 and mixed hematopoietic lineage markers. Collectively, our results highlight synergistic EBV membrane oncoprotein effects on GC B cells and provide a model for studies of their roles in immunosuppression-related lymphoproliferative diseases.

scholarly journals Covalent Linkage of HIV-1 Trimers to Synthetic Liposomes Elicits Improved B Cell and Antibody Responses

2017 ◽  
Vol 91 (16) ◽  
Author(s):  
Shridhar Bale ◽  
Geraldine Goebrecht ◽  
Armando Stano ◽  
Richard Wilson ◽  
Takayuki Ota ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
Neutralizing Antibodies ◽  
Tier 2 ◽  
Covalent Linkage ◽  
His Tag ◽  
Hiv 1

ABSTRACT We have demonstrated that a liposomal array of well-ordered trimers enhances B cell activation, germinal center formation, and the elicitation of tier-2 autologous neutralizing antibodies. Previously, we coupled well-ordered cleavage-independent NFL trimers via their C-terminal polyhistidine tails to nickel lipids integrated into the lipid bilayer. Despite favorable in vivo effects, concern remained over the potentially longer-term in vivo instability of noncovalent linkage of the trimers to the liposomes. Accordingly, we tested both cobalt coupling and covalent linkage of the trimers to the liposomes by reengineering the polyhistidine tail to include a free cysteine on each protomer of model BG505 NFL trimers to allow covalent linkage. Both cobalt and cysteine coupling resulted in a high-density array of NFL trimers that was stable in both 20% mouse serum and 100 mM EDTA, whereas the nickel-conjugated trimers were not stable under these conditions. Binding analysis and calcium flux with anti-Env-specific B cells confirmed that the trimers maintained conformational integrity following coupling. Following immunization of mice, serologic analysis demonstrated that the covalently coupled trimers elicited Env-directed antibodies in a manner statistically significantly improved compared to soluble trimers and nickel-conjugated trimers. Importantly, the covalent coupling not only enhanced gp120-directed responses compared to soluble trimers, it also completely eliminated antibodies directed to the C-terminal His tag located at the “bottom” of the spike. In contrast, soluble and noncovalent formats efficiently elicited anti-His tag antibodies. These data indicate that covalent linkage of well-ordered trimers to liposomes in high-density array displays multiple advantages in vitro and in vivo. IMPORTANCE Enveloped viruses typically encode a surface-bound glycoprotein that mediates viral entry into host cells and is a primary target for vaccine design. Liposomes with modified lipid head groups have a unique feature of capturing and displaying antigens on their surfaces, mimicking the native pathogens. Our first-generation nickel-based liposomes captured HIV-1 Env glycoprotein trimers via a noncovalent linkage with improved efficacy over soluble glycoprotein in activating germinal center B cells and eliciting tier-2 autologous neutralizing antibodies. In this study, we report the development of second-generation cobalt- and maleimide-based liposomes that have improved in vitro stability over nickel-based liposomes. In particular, the maleimide liposomes captured HIV-1 Env trimers via a more stable covalent bond, resulting in enhanced germinal center B cell responses that generated higher antibody titers than the soluble trimers and liposome-bearing trimers via noncovalent linkages. We further demonstrate that covalent coupling prevents release of the trimers prior to recognition by B cells and masks a nonneutralizing determinant located at the bottom of the trimer.

Enforced BCL6 Expression Inhibits B Cell Development in Vivo.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1535-1535
Author(s):  
Davide F. Robbiani ◽  
Kaity Colon ◽  
Kruti Naik ◽  
Helen Nickerson ◽  
Maurizio Affer ◽  
...  
Keyword(s):  
B Cells ◽  
Transgenic Mice ◽  
B Cell ◽  
Light Chain ◽  
Germinal Center ◽  
Regulatory Elements ◽  
Cell Development ◽  
B Cell Development ◽  
Kappa Light Chain

Abstract The B-Cell Lymphoma 6 (BCL6) gene encodes for a zinc finger motifs containing transcriptional repressor that is frequently dysregulated by chromosomal translocations in germinal center lymphomas. A putative protooncogene, its transforming ability in vivo was reported in I-mu-HA-BCL6 knock-in mice by Cattoretti et al last year. We also tested this assumption in transgenic mice expressing BCL6 in B cells under the control of kappa light chain regulatory elements. We replaced the murine C-kappa locus with the 16kb human BCL6 genomic locus in a construct containing the murine kappa light chain regulatory elements (Vk, EiK, 3′RR). While control transgenics were readily obtained (5/32 founders), only 3/68 founders were positive for the BCL6 transgene, of which only one (bearing a single copy of the transgene) was able to transmit the transgene to its progeny, thus suggesting embryonal toxicity of exogenous BCL6. In the bone marrow, flow cytometry revealed a nearly complete block of B cell development at the pro-B to pre-B transition. This was also the stage at which we first detected expression of EGFP in control reporter mice that were generated in parallel. Spleens of transgenic mice weighed about 50% of control spleens and less than 5% of splenocytes were CD19+ B cells. These were IgM high, IgD intermediate, corresponding to an immature B cell phenotype. Lymph nodes were smaller and B cells barely detected. Peyers’ patches were not visible. Combined, our analysis of 6–8 weeks old VkHABCL6 transgenic mice reveals that enforced expression of BCL6 early in development results in a profound block of B lymphocyte differentiation. How transgenic BCL6 modulates this effect at the transcriptional level remains to be investigated. To test the oncogenic potential of BCL6 in B cells, it will be interesting to precisely turn on this gene in the germinal center.

SFRP5 Inhibits Early Stages Of B-Cell Differentiation and Modulates Estrogen-Related Changes In The Immune System

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2422-2422
Author(s):  
Takafumi Yokota ◽  
Kenji Oritani ◽  
Takao Sudo ◽  
Tomohiko Ishibashi ◽  
Yukiko Doi ◽  
...  
Keyword(s):  
Immune System ◽  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
B Lymphocytes ◽  
Molecular Mechanisms ◽  
Adaptive Immune System ◽  
B Cell Differentiation ◽  
B Lymphopoiesis

Abstract A large body of research has demonstrated that the maternal immune system is elaborately regulated during pregnancy to establish immunological tolerance to the fetus. Although our previous works have revealed that female sex hormones, particularly estrogen, play pivotal roles in suppressing maternal B-lymphopoiesis, the precise molecular mechanisms that mediate their functions are largely unknown. Because T and B lymphocytes function coordinately in the adaptive immune system, the inhibition of B-lymphopoiesis during pregnancy should be involved, at least in part, in “maternal-fetal immune tolerance.” Understanding the molecular mechanisms of tolerance would contribute to the development of new methods to inhibit immune responses after organ transplantation, such as rejection by the host or graft-versus-host diseases. The goal of our present study is to identify the molecular pathways through which estrogen exerts its suppressive effect on B-lymphopoiesis. We performed global analyses of estrogen-inducible genes in bone marrow (BM) stromal cells and identified the secreted frizzled-related protein (sFRP) family. A sFRP1-immunoglobulin G (Ig) fusion protein inhibited early differentiation of B-cells originating from BM-derived hematopoietic stem/progenitor cells (HSPC) in culture (Yokota T. et al. Journal of Immunol, 2008). Conversely, sFRP1 deficiency in vivo caused dysregulation of HSPC homeostasis in BM and aberrant increase of peripheral B lymphocytes (Renström J. et al. Cell Stem Cell, 2009). Therefore, in the present study we generated sFRP1 transgenic chimera (TC) mice that produced high levels of circulating sFRP1 after birth to examine the influence of sFRP1 on adult lymphopoiesis in vivo. Further, we generated sFRP5 TC mice using the same procedure to determine whether there were functional differences or redundancies between sFRP1 and sFRP5. The two are most closely related isoforms among the sFRP family and are known to play redundant roles during embryonic development; however, their physiological function in the immune system is largely unknown. Unexpectedly, while only subtle change was detected in the lymphoid lineage of sFRP1 TC mice, we found that the number of B cells was significantly reduced in the sFRP5 TC mice. The frequency of B cells, which normally account for approximately 50% of peripheral leukocytes of wild-type (WT) mice, was reduced to less than 20% in the sFRP5 TC mice. The suppression was likely specific to the B lineage, because overexpression of sFRP5 did not affect myeloid, T, or NK cells. Compared with WT littermates, the body size of sFRP5 TC mice was slightly, but significantly smaller. Thymocyte counts were not affected. In contrast, the number of splenocytes, particularly those of the B lineage, significantly decreased. In BM of sFRP5 TC mice, early B-cell differentiation was inhibited, resulting in the accumulation of cells whose phenotype corresponds to those of common lymphoid progenitors (CLPs). Gene array analyses of the accumulated CLPs indicated that sFRP5 affects the expression of adaptive immune system-related genes. Further, the sFRP5 overexpression was found to induce the expression of Wnt and Notch-related molecules that regulate the integrity of HSPCs. To determine the physiological involvement of sFRP5 in the inhibition of early B-cell differentiation, we exploited mice lacking sFRP5. It is noteworthy that, although the level of sFRP5 expression was minimal in steady-state BM, it was markedly induced after estrogen treatment. We injected water-soluble β-estradiol into WT or sFRP5-null mice for 4 days and evaluated their lympho-hematopoiesis 12 h after the last injection. While the highly HSPC-enriched Lineage- Sca-1+ c-kitHi Flt3- fraction of WT mice was resistant to the treatment, the same fraction of sFRP5-null mice showed a declining trend. Further, although the CLP fraction was significantly reduced in both strains, CLPs of sFRP5-null mice were more sensitive to estrogen than those of WT. We also performed gene expression analyses of WT and sFRP5-null mice after the estrogen treatment. We found that estrogen induced the expression of Hes1 in HSPCs of WT but not sFRP5-null mice. Thus, we conclude that estrogen-inducible sFRP5 blocks the differentiation of HSPCs in BM to B-lymphocytes in the presence of high levels of estrogen, at least in part by activation of the Notch pathway. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Use of a Virus-Encoded Enzymatic Marker Reveals that a Stable Fraction of Memory B Cells Expresses Latency-Associated Nuclear Antigen throughout Chronic Gammaherpesvirus Infection

2010 ◽  
Vol 84 (15) ◽  
pp. 7523-7534 ◽  
Author(s):  
Michael S. Nealy ◽  
Carrie B. Coleman ◽  
Haiyan Li ◽  
Scott A. Tibbetts
Keyword(s):  
B Cells ◽  
Germinal Center ◽  
Maintenance Phase ◽  
Memory B Cells ◽  
Nuclear Antigen ◽  
Murine Gammaherpesvirus ◽  
Barr Virus ◽  
Enzymatic Marker ◽  
Epstein Barr

ABSTRACT An integral feature of gammaherpesvirus infections is the ability to establish lifelong latency in B cells. During latency, the viral genome is maintained as an extrachomosomal episome, with stable maintenance in dividing cells mediated by the viral proteins Epstein-Barr nuclear antigen 1 (EBNA-1) for Epstein-Barr virus and latency-associated nuclear antigen (LANA) for Kaposi's sarcoma-associated herpesvirus. It is believed that the expression of episome maintenance proteins is turned off in the predominant long-term latency reservoir of resting memory B cells, suggesting that chronic gammaherpesvirus infection is primarily dormant. However, the kinetics of LANA/EBNA-1 expression in individual B-cell subsets throughout a course of infection has not been examined. The infection of mice with murine gammaherpesvirus 68 (MHV68, γHV68) provides a model to determine the specific cellular and molecular events that occur in vivo during lifelong gammaherpesvirus latency. In work described here, we make use of a heterologously expressed enzymatic marker to define the types of B cells that express the LANA homolog (mLANA) during chronic MHV68 infection. Our data demonstrate that mLANA is expressed in a stable fraction of B cells throughout chronic infection, with a prominent peak at 28 days. The expression of mLANA was detected in naïve follicular B cells, germinal-center B cells, and memory B cells throughout infection, with germinal-center and memory B cells accounting for more than 80% of the mLANA-expressing cells during the maintenance phase of latency. These findings suggest that the maintenance phase of latency is an active process that involves the ongoing proliferation or reseeding of latently infected memory B cells.

scholarly journals Selective Gene Expression of Latent Murine Gammaherpesvirus 68 in B Lymphocytes

2003 ◽  
Vol 77 (13) ◽  
pp. 7308-7318 ◽  
Author(s):  
Sofia Marques ◽  
Stacey Efstathiou ◽  
K. G. Smith ◽  
Matthias Haury ◽  
J. Pedro Simas
Keyword(s):  
Gene Expression ◽  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
Critical Role ◽  
Murine Gammaherpesvirus ◽  
Virus Transcription ◽  
Gammaherpesvirus 68 ◽  
Murine Gammaherpesvirus 68 ◽  
Germinal Center B Cells

ABSTRACT Intranasal infection of mice with murine gammaherpesvirus 68 (MHV-68), a virus genetically related to the human pathogen Kaposi's sarcoma-associated herpesvirus, results in a persistent, latent infection in the spleen and other lymphoid organs. Here, we have determined the frequency of virus infection in splenic dendritic cells, macrophages, and several B-cell subpopulations, and we quantified cell type-dependent virus transcription patterns. The frequencies of virus genome positive cells were maximal at 14 days postinfection in all splenic cell populations analyzed. Marginal zone and germinal center B cells harbored the highest frequency of infection and the former population accounted for approximately half the total number of infected B cells. Analysis of virus transcription during the establishment of latency revealed that virus gene expression in B cells was restricted and dependent on the differentiation stage of the B cell. Notably, transcription of ORF73 was detected in germinal center B cells, a finding in agreement with the predicted latent genome maintenance function of ORF73 in dividing cells. At late times after infection, virus DNA could only be detected in newly formed and germinal center B cells, which suggests that B cells play a critical role in facilitating life-long latency.

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

2017 ◽  
Vol 91 (19) ◽  
Author(s):  
Eric J. Darrah ◽  
Joseph M. Kulinski ◽  
Wadzanai P. Mboko ◽  
Gang Xin ◽  
Laurent P. Malherbe ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Ataxia Telangiectasia ◽  
Chronic Infection ◽  
Viral Latency ◽  
Viral Reactivation ◽  
Ataxia Telangiectasia Mutated

ABSTRACT 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 myeloid-specific 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 cell-specific ATM expression during chronic gammaherpesvirus infection.

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